1  2277 107 EPIGENETIC REGULATION BY ASXL1 IN MYELOID MALIGNANCIES. MYELOID MALIGNANCIES ARE CLONAL HEMATOPOIETIC DISORDERS THAT ARE COMPRISED OF A SPECTRUM OF GENETICALLY HETEROGENEOUS DISORDERS, INCLUDING MYELODYSPLASTIC SYNDROMES (MDS), MYELOPROLIFERATIVE NEOPLASMS (MPN), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), AND ACUTE MYELOID LEUKEMIA (AML). MYELOID MALIGNANCIES ARE CHARACTERIZED BY EXCESSIVE PROLIFERATION, ABNORMAL SELF-RENEWAL, AND/OR DIFFERENTIATION DEFECTS OF HEMATOPOIETIC STEM CELLS (HSCS) AND MYELOID PROGENITOR CELLS HEMATOPOIETIC STEM/PROGENITOR CELLS (HSPCS). MYELOID MALIGNANCIES CAN BE CAUSED BY GENETIC AND EPIGENETIC ALTERATIONS THAT PROVOKE KEY CELLULAR FUNCTIONS, SUCH AS SELF-RENEWAL, PROLIFERATION, BIASED LINEAGE COMMITMENT, AND DIFFERENTIATION. ADVANCES IN NEXT-GENERATION SEQUENCING LED TO THE IDENTIFICATION OF MULTIPLE MUTATIONS IN MYELOID NEOPLASMS, AND MANY NEW GENE MUTATIONS WERE IDENTIFIED AS KEY FACTORS IN DRIVING THE PATHOGENESIS OF MYELOID MALIGNANCIES. THE POLYCOMB PROTEIN ASXL1 WAS IDENTIFIED TO BE FREQUENTLY MUTATED IN ALL FORMS OF MYELOID MALIGNANCIES, WITH MUTATIONAL FREQUENCIES OF 20%, 43%, 10%, AND 20% IN MDS, CMML, MPN, AND AML, RESPECTIVELY. SIGNIFICANTLY, ASXL1 MUTATIONS ARE ASSOCIATED WITH A POOR PROGNOSIS IN ALL FORMS OF MYELOID MALIGNANCIES. THE FACT THAT ASXL1 MUTATIONS ARE ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH CMML, MDS, AND AML, POINTS TO THE POSSIBILITY THAT ASXL1 MUTATION IS A KEY FACTOR IN THE DEVELOPMENT OF MYELOID MALIGNANCIES. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN UNDERSTANDING MYELOID MALIGNANCIES WITH A SPECIFIC FOCUS ON ASXL1 MUTATIONS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2  6793  27 [DOWN-REGULATION OF TRANSCRIPTION FACTOR PU.1 VIA ABNORMAL EPIGENETIC MODIFICATION IN CHRONIC MYELOID LEUKEMIA]. OBJECTIVE: TO INVESTIGATE THE UNDERLYING MECHANISM AND CLINICAL SIGNIFICANCE OF PU.1 DOWN-EXPRESSION IN CHRONIC MYELOID LEUKEMIA (CML) PATIENTS. METHODS: DIFFERENT METHYLATION STATUS OF PU.1 PROMOTER REGION CONTAINING 20 CPG ISLANDS IN NORMAL INDIVIDUALS, CML CHRONIC PHASE AND BLAST CRISIS PATIENTS, COMPLETE CYTOGENETIC REMISSION PATIENTS AFTER IMATINIB TREATMENT, AND BLAST CRISIS BONE MARROW K562 CML CELLS WAS DETECTED BY BISULFITE SEQUENCING. SEMI-QUANTITATIVE PCR WAS USED TO DETECT THE PU.1 MRNA EXPRESSION IN NORMAL CONTROLS, CML CHRONIC PHASE AND BLAST CRISIS PATIENTS, AND BLAST CRISIS BONE MARROW K562 CML CELLS. INDIRECT IMMUNE FLUORESCENCE AND WESTERN BLOT WERE USED TO ANALYZE THE EXPRTESSION OF PU.1 PROTEIN IN NORMAL INDIVIDUALS, CML CHRONIC PHASE AND BLAST CRISIS PATIENTS, AND BLAST CRISIS BONE MARROW K562 CML CELLS. RESULTS: ABERRANT METHYLATION IN THE PROMOTER REGION OF TRANSCRIPTION FACTOR PU.1 WAS FOUND IN BOTH CML CHRONIC PHASE AND BLAST CRISIS PHASE BONE MARROW CELLS, AS WELL AS IN CML BLAST K562 CELLS. DOWN-EXPRESSION OF PU.1 MRNA AND PROTEIN LEVELS WAS FOUND IN ABOVE CELLS. NO METHYLATION IN THE PROMOTER REGION OF PU.1 WAS OBSERVED IN NORMAL INDIVIDUALS, AND THE PU.1 MRNA AND PROTEIN EXPRESSIONS WERE NOT REDUCED AT ALL. FURTHERMORE, HIGH METHYLATION STATUS OF BONE MARROW CELLS WAS EVEN OBSERVED IN THE CML PATIENTS WHO ACQUIRED COMPLETE CYTOGENETIC REMISSION. CONCLUSIONS: THE RESULTS OF OUR STUDY INDICATE THAT THE EPIGENETIC MODIFICATION OF PU.1 IN CML PATIENTS AND K562 CELL LINE MIGHT BE RESPONSIBLE FOR THE DOWN-EXPRESSION OF PU.1. THE DATA SUGGEST THAT ABERRANT METHYLATION OF PU.1 PLAYS A ROLE IN CML PATHOGENESIS, THEREFORE, IT MIGHT SERVE AS A USEFUL BIOMARKER AND POTENTIAL TARGET IN THERAPY FOR CHRONIC MYELOID LEUKEMIA.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3  6780  33 [BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM ACCOMPANIED BY CHRONIC MYELOMONOCYTIC LEUKEMIA SUCCESSFULLY TREATED WITH AZACITIDINE]. BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN) IS A RARE DISEASE THAT DEVELOPS WITH A SKIN LESION AND IS OFTEN ACCOMPANIED BY LEUKEMIC TRANSFORMATION. THE NORMAL COUNTERPARTS OF BPDCN TUMOR CELLS ARE PROGENITORS OF PLASMACYTOID DENDRITIC CELLS, WHEREAS THE ORIGINS ARE THOUGHT TO BE HEMATOPOIETIC STEM CELLS. APPROXIMATELY 10%-20% OF BPDCN PATIENTS DEVELOP OTHER HEMATOLOGIC MALIGNANCIES, INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). MUTATIONS IN EPIGENETIC REGULATORS ARE FREQUENTLY OBSERVED IN BOTH BPDCN AND CMML TUMORS. AZACITIDINE, A DRUG THAT TARGETS EPIGENETIC DYSREGULATION, IS KNOWN TO BE AN EFFECTIVE TREATMENT FOR CMML. HOWEVER, IT HAS BEEN USED IN FEW BPDCN PATIENTS. HERE, WE REPORT A BPDCN PATIENT WITH SKIN LESIONS, BONE MARROW INFILTRATION, AND LYMPHADENOPATHY. CMML ALSO DEVELOPED DURING THE COURSE OF BPDCN. AZACITIDINE HAD POSITIVE EFFECTS ON CMML; HOWEVER, BPDCN AGGRESSIVELY RELAPSED DURING TREATMENT. TWO TET2 MUTATIONS WERE FOUND IN BOTH BPDCN AND CMML TUMORS; ONE OF WHICH WAS COMMONLY IDENTIFIED IN BOTH TUMORS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
4  4557  36 MUTATIONS IN ASXL1 ARE ASSOCIATED WITH POOR PROGNOSIS ACROSS THE SPECTRUM OF MALIGNANT MYELOID DISEASES. THE ASXL1 GENE IS ONE OF THE MOST FREQUENTLY MUTATED GENES IN MALIGNANT MYELOID DISEASES. THE ASXL1 PROTEIN BELONGS TO PROTEIN COMPLEXES INVOLVED IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. ASXL1 MUTATIONS ARE FOUND IN MYELOPROLIFERATIVE NEOPLASMS (MPN), MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ACUTE MYELOID LEUKEMIA (AML). THEY ARE GENERALLY ASSOCIATED WITH SIGNS OF AGGRESSIVENESS AND POOR CLINICAL OUTCOME. BECAUSE OF THIS, A SYSTEMATIC DETERMINATION OF ASXL1 MUTATIONAL STATUS IN MYELOID MALIGNANCIES SHOULD HELP IN PROGNOSIS ASSESSMENT.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5  5911  35 TARGETED NEXT-GENERATION SEQUENCING IN MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA AIDS DIAGNOSIS IN CHALLENGING CASES AND IDENTIFIES FREQUENT SPLICEOSOME MUTATIONS IN TRANSFORMED ACUTE MYELOID LEUKEMIA. OBJECTIVES: OPTIMAL INTEGRATION OF NEXT-GENERATION SEQUENCING (NGS) INTO CLINICAL PRACTICE IN HEMATOLOGIC MALIGNANCIES REMAINS UNCLEAR. WE EVALUATE THE UTILITY OF NGS IN MYELOID MALIGNANCIES. METHODS: A 42-GENE PANEL WAS USED TO SEQUENCE 109 CASES OF MYELODYSPLASTIC SYNDROME (MDS, N = 38), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML, N = 14), MYELOPROLIFERATIVE NEOPLASM (MPN, N = 24), AND MDS AND/OR MPN TRANSFORMED TO ACUTE MYELOID LEUKEMIA (AML, N = 33). RESULTS: AT LEAST ONE PATHOGENIC MUTATION WAS IDENTIFIED IN 74% OF CASES OF MDS, 100% OF CMMLS, AND 96% OF MPNS. IN CONTRAST, ONLY 47% OF CASES OF MDS (18/38) AND 7% (1/14) OF CMMLS EXHIBITED ABNORMAL CYTOGENETICS. IN DIAGNOSTICALLY DIFFICULT CASES OF MDS OR CMML WITH NORMAL CYTOGENETICS, NGS IDENTIFIED A PATHOGENIC MUTATION AND WAS CRITICAL IN ESTABLISHING THE CORRECT DIAGNOSIS. SPLICEOSOMAL GENES AND EPIGENETIC MODIFIERS WERE FREQUENTLY MUTATED. SPLICEOSOME MUTATIONS WERE ALSO FREQUENTLY DETECTED IN AML ARISING FROM MDS, CMML, OR MPN (39%) COMPARED WITH THE REPORTED RATE IN DE NOVO AML (7%-14%). CONCLUSIONS: IN DIFFICULT CASES OF MDS OR MPN, NGS FACILITATES DIAGNOSIS BY DETECTION OF GENE MUTATIONS TO CONFIRM CLONALITY, AND AMLS EVOLVING FROM MDS OR MPN CARRY FREQUENT MUTATIONS IN SPLICEOSOMAL GENES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6  3530  26 IMATINIB (ST1571) PROVIDES ONLY LIMITED SELECTIVITY FOR CML CELLS AND TREATMENT MIGHT BE COMPLICATED BY SILENT BCR-ABL GENES. VERY PROMISING RESULTS HAVE BEEN OBTAINED IN CLINICAL TRIALS ON CHRONIC-PHASE CHRONIC MYELOID LEUKEMIA (CP-CML) PATIENTS TREATED WITH IMATINIB MESYLATE (IM; GLEEVECR, STI571), A BCR-ABL TYROSINE KINASE INHIBITOR. HOWEVER, WE FOUND THAT IM CAUSED CONSIDERABLE INHIBITION OF NORMAL HEMATOPOIETIC PROGENITOR CELLS UPON TREATING CONTROL BONE MARROW (BM) CULTURES. IN VITRO IM TREATMENT GAVE A DECREASE IN THE YIELD AND SIZE OF COLONIES FROM BM OF UNTREATED CP-CML PATIENTS THAT WAS ONLY TWO TO THREE TIMES THAT FROM THE NORMAL SAMPLES. MOREOVER, ABOUT 30% OF MYELOID PROGENITORS (CFU-GM) FROM CML BM STILL FORMED COLONIES IN THE PRESENCE OF IM, MOST OF WHICH HAD BCR-ABL RNA. ABOUT HALF OF THESE TREATED COLONIES ALSO DISPLAYED METHYLATION OF THE INTERNAL ABL PA PROMOTER, A CML-SPECIFIC EPIGENETIC ALTERATION, WHICH WAS USED IN THIS STUDY AS A MARKER FOR BCR-ABL TRANSLOCATION-CONTAINING CELLS. HOWEVER, ~5-8% OF THE TREATED OR THE UNTREATED CML BM-DERIVED COLONIES HAD NO DETECTABLE BCR-ABL RNA BY TWO OR THREE ROUNDS OF RT-PCR DESPITE BEING POSITIVE FOR THE INTERNAL STANDARD RNA AND DISPLAYING HALLMARKS OF CML, EITHER T(9;22)(Q34;QL 1) OR ABL PA METHYLATION. OUR RESULTS INDICATE THAT IM IS ONLY PARTIALLY SPECIFIC FOR CML PROGENITOR CELLS COMPARED TO NORMAL HEMATOPOIETIC PROGENITOR CELLS AND SUGGEST THAT SOME CML CELLS MAY HAVE A SILENT BCR-ABL ONCOGENE THAT COULD INTERFERE WITH THERAPY.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  4748  40 NOVEL MUTATIONS AND THEIR FUNCTIONAL AND CLINICAL RELEVANCE IN MYELOPROLIFERATIVE NEOPLASMS: JAK2, MPL, TET2, ASXL1, CBL, IDH AND IKZF1. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ORIGINATE FROM GENETICALLY TRANSFORMED HEMATOPOIETIC STEM CELLS THAT RETAIN THE CAPACITY FOR MULTILINEAGE DIFFERENTIATION AND EFFECTIVE MYELOPOIESIS. BEGINNING IN EARLY 2005, A NUMBER OF NOVEL MUTATIONS INVOLVING JANUS KINASE 2 (JAK2), MYELOPROLIFERATIVE LEUKEMIA VIRUS (MPL), TET ONCOGENE FAMILY MEMBER 2 (TET2), ADDITIONAL SEX COMBS-LIKE 1 (ASXL1), CASITAS B-LINEAGE LYMPHOMA PROTO-ONCOGENE (CBL), ISOCITRATE DEHYDROGENASE (IDH) AND IKAROS FAMILY ZINC FINGER 1 (IKZF1) HAVE BEEN DESCRIBED IN BCR-ABL1-NEGATIVE MPNS. HOWEVER, NONE OF THESE MUTATIONS WERE MPN SPECIFIC, DISPLAYED MUTUAL EXCLUSIVITY OR COULD BE TRACED BACK TO A COMMON ANCESTRAL CLONE. JAK2 AND MPL MUTATIONS APPEAR TO EXERT A PHENOTYPE-MODIFYING EFFECT AND ARE DISTINCTLY ASSOCIATED WITH POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA AND PRIMARY MYELOFIBROSIS; THE CORRESPONDING MUTATIONAL FREQUENCIES ARE APPROXIMATELY 99, 55 AND 65% FOR JAK2 AND 0, 3 AND 10% FOR MPL MUTATIONS. THE INCIDENCE OF TET2, ASXL1, CBL, IDH OR IKZF1 MUTATIONS IN THESE DISORDERS RANGES FROM 0 TO 17%; THESE LATTER MUTATIONS ARE MORE COMMON IN CHRONIC (TET2, ASXL1, CBL) OR JUVENILE (CBL) MYELOMONOCYTIC LEUKEMIAS, MASTOCYTOSIS (TET2), MYELODYSPLASTIC SYNDROMES (TET2, ASXL1) AND SECONDARY ACUTE MYELOID LEUKEMIA, INCLUDING BLAST-PHASE MPN (IDH, ASXL1, IKZF1). THE FUNCTIONAL CONSEQUENCES OF MPN-ASSOCIATED MUTATIONS INCLUDE UNREGULATED JAK-STAT (JANUS KINASE/SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION) SIGNALING, EPIGENETIC MODULATION OF TRANSCRIPTION AND ABNORMAL ACCUMULATION OF ONCOPROTEINS. HOWEVER, IT IS NOT CLEAR AS TO WHETHER AND HOW THESE ABNORMALITIES CONTRIBUTE TO DISEASE INITIATION, CLONAL EVOLUTION OR BLASTIC TRANSFORMATION.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8    32  37 A CASE OF TYROSINE KINASE INHIBITOR-RESISTANT CHRONIC MYELOID LEUKEMIA, CHRONIC PHASE WITH ASXL1 MUTATION. HEMATOLOGICAL MALIGNANCIES, INCLUDING CHRONIC MYELOID LEUKEMIA (CML), EXHIBIT ASXL1 MUTATIONS; HOWEVER, THE FUNCTION AND MOLECULAR MECHANISM OF THESE MUTATIONS REMAIN UNCLEAR. ASXL1 WAS ORIGINALLY IDENTIFIED AS TUMOR SUPPRESSOR GENE, IN WHICH LOSS OF FUNCTION CAUSES MYELODYSPLASTIC SYNDROME (MDS). ASXL1 MUTATIONS ARE COMMON AND ASSOCIATED WITH DISEASE PROGRESSION IN MYELOID MALIGNANCIES INCLUDING MDS, ACUTE MYELOID LEUKEMIA, AND SIMILARLY IN CML. IN MDS, ASXL1 MUTATIONS HAVE BEEN ASSOCIATED WITH POOR PROGNOSIS; HOWEVER, THE IMPACT OF ASXL1 MUTATIONS IN CML HAS NOT BEEN WELL DESCRIBED. A 31-YEAR-OLD MALE WAS DIAGNOSED AS CML-CHRONIC PHASE (CP). LABORATORY FINDINGS SHOWED A WHITE BLOOD CELL COUNT OF 187,200/MICROL, WITH ASYMPTOMATIC SPLENOMEGALY. BLAST COUNT WAS 5.0% IN PERIPHERAL BLOOD AND 7.3% IN BONE MARROW. THERE WAS NO ADDITIONAL CHROMOSOMAL ABNORMALITY EXCEPT FOR T(9;22)(Q34;Q11.2) BY CHROMOSOMAL ANALYSIS. AT ONSET, THE SOKAL SCORE WAS 1.4, INDICATING HIGH RISK. THE PATIENT RECEIVED TYROSINE KINASE INHIBITOR (TKI) THERAPY, COMPRISING NILOTINIB APPROXIMATELY 600 MG/DAY, BOSUTINIB APPROXIMATELY 600 MG/DAY, PONATINIB APPROXIMATELY 45 MG/DAY, AND DASATINIB APPROXIMATELY 100 MG/DAY. NEVERTHELESS, AFTER 1.5 YEARS OF CONTINUOUS TKI THERAPY, THE BEST OUTCOME WAS A HEMATOLOGICAL RESPONSE. ALTHOUGH ADDITIONAL CHROMOSOMAL ABERRATIONS AND ABL1 KINASE MUTATIONS WERE ANALYZED REPEATEDLY BEFORE AND DURING TKI THERAPY, KNOWN GENETIC ABNORMALITIES WERE NOT DETECTED. THEREAFTER, THE PATIENT UNDERWENT BONE MARROW TRANSPLANTATION FROM AN HLA 7/8 MATCHED UNRELATED DONOR (HLA-CW 1 LOCUS MISMATCH, GRAFT-VERSUS-HOST DIRECTION). THE PATIENT ACHIEVED NEUTROPHIL ENGRAFTMENT, 18 DAYS AFTER TRANSPLANTATION, LEADING TO COMPLETE REMISSION WITH AN UNDETECTABLE LEVEL OF BCR-ABL1 MRNA. THE PATIENT, HOWEVER, DIED FROM GRAFT-VERSUS-HOST DISEASE AND THROMBOTIC MICROANGIOPATHY AFTER 121 DAYS. GENE SEQUENCE ANALYSIS OF HIS CML CELL BEFORE STEM CELL TRANSPLANTATION REVEALED ASXL1 MUTATIONS. PHYSIOLOGICALLY, ASXL1 CONTRIBUTES TO EPIGENETIC REGULATION. IN THE CML-CP PATIENT IN THIS CASE REPORT, ASXL1 MUTATION CONFERRED RESISTANCE TO TKI THROUGH OBSCURE RESISTANCE MECHANISMS. EVEN THOUGH A MOLECULAR MECHANISM FOR TKI RESISTANCE IN ASXL1 MUTATION IN CML HAS REMAINED OBSCURE, EPIGENETIC MODULATION IS A PLAUSIBLE MODE OF CML DISEASE PROGRESSION. THE CLINICAL IMPACT INCLUDING PROGNOSIS OF ASXL1 FOR CML IS UNDERSCORED. AND THE TREATMENT STRATEGY OF CML WITH ASXL1 MUTATION HAS NOT BEEN ESTABLISHED. A DISCUSSION OF THIS CASE WAS EXPECTED TO FACILITATE TREATMENT OPTIONS.	2020	

9   690  30 BRD4 DEGRADATION BLOCKS EXPRESSION OF MYC AND MULTIPLE FORMS OF STEM CELL RESISTANCE IN PH(+) CHRONIC MYELOID LEUKEMIA. IN MOST PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) CLONAL CELLS CAN BE KEPT UNDER CONTROL BY BCR::ABL1 TYROSINE KINASE INHIBITORS (TKI). HOWEVER, OVERT RESISTANCE OR INTOLERANCE AGAINST THESE TKI MAY OCCUR. WE IDENTIFIED THE EPIGENETIC READER BRD4 AND ITS DOWNSTREAM-EFFECTOR MYC AS GROWTH REGULATORS AND THERAPEUTIC TARGETS IN CML CELLS. BRD4 AND MYC WERE FOUND TO BE EXPRESSED IN PRIMARY CML CELLS, CD34(+) /CD38(-) LEUKEMIC STEM CELLS (LSC), AND IN THE CML CELL LINES KU812, K562, KCL22, AND KCL22(T315I) . THE BRD4-TARGETING DRUG JQ1 WAS FOUND TO SUPPRESS PROLIFERATION IN KU812 CELLS AND PRIMARY LEUKEMIC CELLS IN THE MAJORITY OF PATIENTS WITH CHRONIC PHASE CML. IN THE BLAST PHASE OF CML, JQ1 WAS LESS EFFECTIVE. HOWEVER, THE BRD4 DEGRADER DBET6 WAS FOUND TO BLOCK PROLIFERATION AND/OR SURVIVAL OF PRIMARY CML CELLS IN ALL PATIENTS TESTED, INCLUDING BLAST PHASE CML AND CML CELLS EXHIBITING THE T315I VARIANT OF BCR::ABL1. MOREOVER, DBET6 WAS FOUND TO BLOCK MYC EXPRESSION AND TO SYNERGIZE WITH BCR::ABL1 TKI IN INHIBITING THE PROLIFERATION IN THE JQ1-RESISTANT CELL LINE K562. FURTHERMORE, BRD4 DEGRADATION WAS FOUND TO OVERCOME OSTEOBLAST-INDUCED TKI RESISTANCE OF CML LSC IN A CO-CULTURE SYSTEM AND TO BLOCK INTERFERON-GAMMA-INDUCED UPREGULATION OF THE CHECKPOINT ANTIGEN PD-L1 IN LSC. FINALLY, DBET6 WAS FOUND TO SUPPRESS THE IN VITRO SURVIVAL OF CML LSC AND THEIR ENGRAFTMENT IN NSG MICE. TOGETHER, TARGETING OF BRD4 AND MYC THROUGH BET DEGRADATION SENSITIZES CML CELLS AGAINST BCR::ABL1 TKI AND IS A POTENT APPROACH TO OVERCOME MULTIPLE FORMS OF DRUG RESISTANCE IN CML LSC.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
10  3878  39 KDM6B OVEREXPRESSION ACTIVATES INNATE IMMUNE SIGNALING AND IMPAIRS HEMATOPOIESIS IN MICE. KDM6B IS AN EPIGENETIC REGULATOR THAT MEDIATES TRANSCRIPTIONAL ACTIVATION DURING DIFFERENTIATION, INCLUDING IN BONE MARROW (BM) HEMATOPOIETIC STEM AND PROGENITOR CELLS (HSPCS). OVEREXPRESSION OF KDM6B HAS BEEN REPORTED IN BM HSPCS OF PATIENTS WITH MYELODYSPLASTIC SYNDROMES (MDS) AND CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). WHETHER THE OVEREXPRESSION OF KDM6B CONTRIBUTES TO THE PATHOGENESIS OF THESE DISEASES REMAINS TO BE ELUCIDATED. TO STUDY THIS, WE GENERATED A VAV-KDM6B MOUSE MODEL, WHICH OVEREXPRESSES KDM6B IN THE HEMATOPOIETIC COMPARTMENT. KDM6B OVEREXPRESSION ALONE LED TO MILD HEMATOPOIETIC PHENOTYPE, AND CHRONIC INNATE IMMUNE STIMULATION OF VAV-KDM6B MICE WITH THE TOLL-LIKE RECEPTOR (TLR) LIGAND LIPOPOLYSACCHARIDE (LPS) RESULTED IN SIGNIFICANT HEMATOPOIETIC DEFECTS. THESE DEFECTS RECAPITULATED FEATURES OF MDS AND CMML, INCLUDING LEUKOPENIA, DYSPLASIA, AND COMPROMISED REPOPULATING FUNCTION OF BM HSPCS. TRANSCRIPTOME STUDIES INDICATED THAT KDM6B OVEREXPRESSION ALONE COULD LEAD TO ACTIVATION OF DISEASE-RELEVANT GENES SUCH AS S100A9 IN BM HSPCS, AND WHEN COMBINED WITH INNATE IMMUNE STIMULATION, KDM6B OVEREXPRESSION RESULTED IN MORE PROFOUND OVEREXPRESSION OF INNATE IMMUNE AND DISEASE-RELEVANT GENES, INDICATING THAT KDM6B WAS INVOLVED IN THE ACTIVATION OF INNATE IMMUNE SIGNALING IN BM HSPCS. FINALLY, PHARMACOLOGIC INHIBITION OF KDM6B WITH THE SMALL MOLECULE INHIBITOR GSK-J4 AMELIORATED THE INEFFECTIVE HEMATOPOIESIS OBSERVED IN VAV-KDM6B MICE. THIS EFFECT WAS ALSO OBSERVED WHEN GSK-J4 WAS APPLIED TO THE PRIMARY BM HSPCS OF PATIENTS WITH MDS BY IMPROVING THEIR REPOPULATING FUNCTION. THESE RESULTS INDICATE THAT OVEREXPRESSION OF KDM6B MEDIATES ACTIVATION OF INNATE IMMUNE SIGNALS AND HAS A ROLE IN MDS AND CMML PATHOGENESIS, AND THAT KDM6B TARGETING HAS THERAPEUTIC POTENTIAL IN THESE MYELOID DISORDERS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11  1901  28 ENGRAFTMENT OF CHRONIC MYELOMONOCYTIC LEUKEMIA CELLS IN IMMUNOCOMPROMISED MICE SUPPORTS DISEASE DEPENDENCY ON CYTOKINES. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A CLONAL HEMATOPOIETIC STEM CELL DISORDER THAT TYPICALLY ASSOCIATES WITH MUTATIONS IN EPIGENETIC, SPLICING, AND SIGNALING GENES. GENETICALLY MODIFIED MOUSE MODELS ONLY PARTIALLY RECAPITULATE THE DISEASE PHENOTYPE, WHEREAS XENOTRANSPLANTATION OF CMML CELLS IN IMMUNOCOMPROMISED MICE HAS BEEN RARELY SUCCESSFUL SO FAR. HERE, CMML CD34(+) CELLS SORTED FROM PATIENT BONE MARROW (BM) OR PERIPHERAL BLOOD (PB) WERE INJECTED INTRAVENOUSLY INTO NSG (NOD/LTSZ-SCID IL2RGAMMANULL) MICE AND NSG MICE ENGINEERED TO EXPRESS HUMAN GRANULO-MONOCYTE COLONY-STIMULATING FACTOR, STEM CELL FACTOR, AND INTERLEUKIN-3 (NSGS MICE). FIFTEEN OUT OF 16 PATIENT SAMPLES (94%) SUCCESSFULLY ENGRAFTED INTO NSG OR NSGS OR BOTH MOUSE STRAINS. THE EXPANSION OF HUMAN CELLS, PREDOMINANT IN THE BM, WAS ALSO OBSERVED IN THE SPLEEN AND THE PB AND WAS GREATLY ENHANCED IN MICE PRODUCING THE 3 HUMAN CYTOKINES. GENE MUTATIONS IDENTIFIED IN ENGRAFTED CELLS WERE MOSTLY SIMILAR TO THOSE IDENTIFIED IN PATIENT CELLS BEFORE INJECTION. SUCCESSFUL SECONDARY ENGRAFTMENT WAS OBTAINED IN NSGS MICE IN 3 OUT OF 10 ATTEMPTS. THUS, PRIMARY CMML LEUKEMIC CELLS EXPAND MUCH BETTER IN NSGS COMPARED WITH NSG MICE WITH LIMITED EFFICACY OF SECONDARY TRANSPLANT.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12  6856  34 [NOT AVAILABLE]. BIOLOGICAL ASPECTS OF JAK/STAT SIGNALING IN BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: MYELOPROLIFERATIVE DISORDERS MORE RECENTLY NAMED MYELOPROLIFERATIVE NEOPLASMS (MPN) DISPLAY SEVERAL CLINICAL ENTITIES: CHRONIC MYELOID LEUKEMIA (CML), THE CLASSICAL MPN INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET), PRIMARY MYELOFIBROSIS (PMF) AND ATYPICAL AND UNCLASSIFIABLE NMP. THE TERM MPN IS MOSTLY USED FOR CLASSICAL BCR-ABL-NEGATIVE (MYELOPROLIFERATIVE DISORDER) (ET, PV, PMF). THESE ARE CLONAL DISEASES RESULTING FROM THE TRANSFORMATION OF AN HEMATOPOIETIC STEM CELL AND LEADING TO AN ABNORMAL PRODUCTION OF MYELOID CELLS. THE GENETIC DEFECTS RESPONSIBLE FOR THE MYELOPROLIFERATIVE ABNORMALITIES ARE CALLED << DRIVER >> MUTATIONS AND ALL RESULT IN DEREGULATION OF THE CYTOKINE RECEPTOR / JAK2 / STAT AXIS. AMONG THEM, JAK2, THE THROMBOPOIETIN RECEPTOR (MPL) AND CALRETICULIN (CALR) MUTATIONS ARE FOUND IN AROUND 90% OF THE CASES. THESE DRIVER MPN MUTATIONS CAN BE ASSOCIATED WITH OTHER DRIVER MUTATIONS ALSO FOUND IN OTHER HEMATOLOGICAL MALIGNANCIES, ESPECIALLY IN PMFS. THESE ARE CHRONIC DISEASES WITH MAJOR RISKS BEING THROMBOSIS, HEMORRHAGE AND CYTOPENIAS FOR PMF AND THE LONG-TERM PROGRESSION TO MYELOFIBROSIS AND THE TRANSFORMATION TO LEUKEMIA. MOST RECENT THERAPEUTIC HAVE FOCUSED ON TARGETING THE JAK2 SIGNALING PATHWAY DIRECTLY BY INHIBITORS OF JAK2 OR INDIRECTLY. INTERFERON A ALLOWS IN SOME CASES HEMATOLOGIC AND MOLECULAR REMISSION PATIENTS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  6079  29 THE EFFECT OF CXCL12 PROCESSING ON CD34+ CELL MIGRATION IN MYELOPROLIFERATIVE NEOPLASMS. PRIMARY MYELOFIBROSIS (PMF) AND POLYCYTHEMIA VERA (PV) ARE CHRONIC MYELOPROLIFERATIVE NEOPLASMS. PMF AND, TO A LESSER DEGREE, PV ARE CHARACTERIZED BY CONSTITUTIVE MOBILIZATION OF HEMATOPOIETIC STEM CELLS (HSC) AND PROGENITOR CELLS (HPC) INTO THE PERIPHERAL BLOOD (PB). THE INTERACTION BETWEEN THE CHEMOKINE CXCL12 AND ITS RECEPTOR CXCR4 PLAYS A PIVOTAL ROLE IN DETERMINING THE TRAFFICKING OF CD34(+) CELLS BETWEEN THE BONE MARROW (BM) AND THE PB. PMF, BUT NOT PV, IS ASSOCIATED WITH DOWNREGULATION OF CXCR4 BY CD34(+) CELLS DUE TO EPIGENETIC EVENTS. BOTH PV AND PMF PATIENTS HAVE ELEVATED LEVELS OF IMMUNOREACTIVE FORMS OF CXCL12 IN THE BM AND PB. USING ELECTROSPRAY MASS SPECTROMETRY, THE PB AND BM PLASMA OF PV AND PMF PATIENTS WAS SHOWN TO CONTAIN REDUCED AMOUNTS OF INTACT CXCL12 BUT SIGNIFICANT AMOUNTS OF SEVERAL TRUNCATED FORMS OF CXCL12, WHICH ARE LACKING IN NORMAL PB AND BM PLASMA. THESE TRUNCATED FORMS OF CXCL12 ARE THE PRODUCT OF THE ACTION OF SEVERAL SERINE PROTEASES, INCLUDING DIPEPTIDYL PEPTIDASE-IV, NEUTROPHIL ELASTASE, MATRIX METALLOPROTEINASE-2 (MMP-2), MMP-9, AND CATHEPSIN G. UNLIKE CXCL12, THESE TRUNCATES EITHER LACK THE ABILITY TO ACT AS A CHEMOATTRACTANT FOR CD34(+) CELLS AND/OR ACT AS AN ANTAGONIST TO THE ACTION OF CXCL12. THESE DATA SUGGEST THAT PROTEOLYTIC DEGRADATION OF CXCL12 IS CHARACTERISTIC OF BOTH PV AND PMF AND THAT THE RESULTING TRUNCATED FORMS OF CXCL12, IN ADDITION TO THE REDUCED EXPRESSION OF CXCR4 BY CD34(+) CELLS, LEAD TO A PROFOUND MOBILIZATION OF HSC/HPC IN PMF.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14  5319  26 PTEN IS FUNDAMENTAL FOR ELIMINATION OF LEUKEMIA STEM CELLS MEDIATED BY GSK126 TARGETING EZH2 IN CHRONIC MYELOGENOUS LEUKEMIA. PURPOSE: LEUKEMIA STEM CELLS (LSCS) ARE AN IMPORTANT SOURCE OF TYROSINE KINASE INHIBITOR RESISTANCE AND DISEASE RELAPSE IN PATIENTS WITH CHRONIC MYELOGENOUS LEUKEMIA (CML). TARGETING LSCS MAY BE AN ATTRACTIVE STRATEGY TO OVERRIDE THIS THORNY PROBLEM. GIVEN THAT EZH2 WAS OVEREXPRESSED IN PRIMARY CML CD34(+) CELLS, OUR PURPOSE IN THIS STUDY WAS TO EVALUATE THE EFFECTS OF TARGETING EZH2 ON CML LSCS AND CLARIFY ITS UNDERLYING MECHANISM.EXPERIMENTAL DESIGN: HUMAN PRIMARY CML CD34(+) CELLS AND RETROVIRALLY BCR-ABL-DRIVEN CML MOUSE MODELS WERE EMPLOYED TO EVALUATE THE EFFECTS OF SUPPRESSION OF EZH2 BY GSK126- OR EZH2-SPECIFIC SHRNA IN VITRO AND IN VIVO RECRUITMENT OF EZH2 AND H3K27ME3 ON THE PROMOTER OF TUMOR-SUPPRESSOR GENE PTEN IN CML CELLS WAS MEASURED BY CHROMATIN IMMUNOPRECIPITATION ASSAY.RESULTS: OUR RESULTS SHOWED THAT PHARMACOLOGIC INHIBITION OF EZH2 BY GSK126 NOT ONLY ELICITED APOPTOSIS AND RESTRICTED CELL GROWTH IN CML BULK LEUKEMIA CELLS, BUT ALSO DECREASED LSCS IN CML CD34(+) CELLS WHILE SPARING THOSE FROM NORMAL BONE MARROW CD34(+) CELLS. SUPPRESSION OF EZH2 BY GSK126 OR SPECIFIC SHRNA PROLONGED SURVIVAL OF CML MICE AND REDUCED THE NUMBER OF LSCS IN MICE. EZH2 KNOCKDOWN RESULTED IN ELEVATION OF PTEN AND LED TO IMPAIRED RECRUITMENT OF EZH2 AND H3K27ME3 ON THE PROMOTER OF PTEN GENE. THE EFFECT OF EZH2 KNOCKDOWN IN THE CML MICE WAS AT LEAST PARTIALLY REVERSED BY PTEN KNOCKDOWN.CONCLUSIONS: THESE FINDINGS IMPROVE THE UNDERSTANDING OF THE EPIGENETIC REGULATION OF STEMNESS IN CML LSCS AND WARRANT CLINICAL TRIAL OF GSK126 IN REFRACTORY PATIENTS WITH CML. CLIN CANCER RES; 24(1); 145-57. (C)2017 AACR.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  1184  25 COOPERATIVE EPIGENETIC REMODELING BY TET2 LOSS AND NRAS MUTATION DRIVES MYELOID TRANSFORMATION AND MEK INHIBITOR SENSITIVITY. MUTATIONS IN EPIGENETIC MODIFIERS AND SIGNALING FACTORS OFTEN CO-OCCUR IN MYELOID MALIGNANCIES, INCLUDING TET2 AND NRAS MUTATIONS. CONCURRENT TET2 LOSS AND NRAS(G12D) EXPRESSION IN HEMATOPOIETIC CELLS INDUCED MYELOID TRANSFORMATION, WITH A FULLY PENETRANT, LETHAL CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), WHICH WAS SERIALLY TRANSPLANTABLE. TET2 LOSS AND NRAS MUTATION COOPERATIVELY LED TO DECREASE IN NEGATIVE REGULATORS OF MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) ACTIVATION, INCLUDING SPRY2, THEREBY CAUSING SYNERGISTIC ACTIVATION OF MAPK SIGNALING BY EPIGENETIC SILENCING. TET2/NRAS DOUBLE-MUTANT LEUKEMIA SHOWED PREFERENTIAL SENSITIVITY TO MAPK KINASE (MEK) INHIBITION IN BOTH MOUSE MODEL AND PATIENT SAMPLES. THESE DATA PROVIDE INSIGHTS INTO HOW EPIGENETIC AND SIGNALING MUTATIONS COOPERATE IN MYELOID TRANSFORMATION AND PROVIDE A RATIONALE FOR MECHANISM-BASED THERAPY IN CMML PATIENTS WITH THESE HIGH-RISK GENETIC LESIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
16  4562  39 MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROMES: A FOCUSED REVIEW. MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) OVERLAP SYNDROMES ARE UNIQUE MYELOID NEOPLASMS, WITH OVERLAPPING FEATURES OF MDS AND MPN. THEY CONSIST OF FOUR ADULT ONSET ENTITIES INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), MDS/MPN-RING SIDEROBLASTS-THROMBOCYTOSIS (MDS/MPN-RS-T), BCR-ABL1 NEGATIVE ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) AND MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U); WITH JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) BEING THE ONLY PEDIATRIC ONSET ENTITY. AMONG THESE OVERLAP NEOPLASMS, CMML IS THE MOST FREQUENT AND IS HALLMARKED BY THE PRESENCE OF SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS WITH RECURRENT MUTATIONS INVOLVING TET2 (60%), SRSF2 (50%) AND ASXL1 (40%); WITH RAS PATHWAY MUTATIONS AND JAK2V617F BEING RELATIVELY ENRICHED IN PROLIFERATIVE CMML SUBTYPES (WBC >/=13 X 109/L). CMML USUALLY PRESENTS IN THE 7TH DECADE OF LIFE, WITH A MALE PREPONDERANCE AND IS ASSOCIATED WITH A MEDIAN OVERALL SURVIVAL OF <36 MONTHS. ADVERSE PROGNOSTICATORS IN CMML INCLUDE INCREASING AGE, HIGH WBC, PRESENCE OF CIRCULATING IMMATURE MYELOID CELLS, ANEMIA, THROMBOCYTOPENIA AND TRUNCATING ASXL1 MUTATIONS. WHILE ALLOGENEIC STEM CELL TRANSPLANTATION REMAINS THE ONLY CURATIVE OPTION, GIVEN THE LATE ONSET OF THIS NEOPLASM AND HIGH FREQUENCY OF COMORBIDITIES, MOST PATIENTS REMAIN INELIGIBLE. HYPOMETHYLATING AGENTS SUCH AS AZACITIDINE, DECITABINE AND ORAL DECITABINE/CEDAZURIDINE HAVE BEEN US FDA APPROVED FOR THE MANAGEMENT OF CMML, WITH OVERALL RESPONSE RATES OF 40-50% AND COMPLETE REMISSION RATES OF <20%. WHILE THESE AGENTS EPIGENETICALLY RESTORE HEMATOPOIESIS IN A SUBSET OF RESPONDING PATIENTS, THEY DO NOT IMPACT MUTATIONAL ALLELE BURDENS AND EVENTUAL DISEASE PROGRESSION TO AML REMAINS INEVITABLE. NEWER TREATMENT MODALITIES EXPLOITING EPIGENETIC, SIGNALING AND SPLICING ABNORMALITIES COMMONLY SEEN IN CMML ARE MUCH NEEDED.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  4485  34 MOLECULAR SIMILARITY BETWEEN MYELODYSPLASTIC FORM OF CHRONIC MYELOMONOCYTIC LEUKEMIA AND REFRACTORY ANEMIA WITH RING SIDEROBLASTS. CHRONIC MYELOMONOCYTIC LEUKEMIA IS SIMILAR TO BUT A SEPARATE ENTITY FROM BOTH MYELOPROLIFERATIVE NEOPLASMS AND MYELODYSPLASTIC SYNDROMES, AND SHOWS EITHER MYELOPROLIFERATIVE OR MYELODYSPLASTIC FEATURES. WE ASK WHETHER THIS DISTINCTION MAY HAVE A MOLECULAR BASIS. WE ESTABLISHED THE GENE EXPRESSION PROFILES OF 39 SAMPLES OF CHRONIC MYELOMONOCYTIC LEUKEMIA (INCLUDING 12 CD34-POSITIVE) AND 32 CD34-POSITIVE SAMPLES OF MYELODYSPLASTIC SYNDROMES BY USING AFFYMETRIX MICROARRAYS, AND STUDIED THE STATUS OF 18 GENES BY SANGER SEQUENCING AND ARRAY-COMPARATIVE GENOMIC HYBRIDIZATION IN 53 SAMPLES. ANALYSIS OF 12 MRNAS FROM CHRONIC MYELOMONOCYTIC LEUKEMIA ESTABLISHED A GENE EXPRESSION SIGNATURE OF 122 PROBE SETS DIFFERENTIALLY EXPRESSED BETWEEN PROLIFERATIVE AND DYSPLASTIC CASES OF CHRONIC MYELOMONOCYTIC LEUKEMIA. AS COMPARED TO PROLIFERATIVE CASES, DYSPLASTIC CASES OVER-EXPRESSED GENES INVOLVED IN RED BLOOD CELL BIOLOGY. WHEN APPLIED TO 32 MYELODYSPLASTIC SYNDROMES, THIS GENE EXPRESSION SIGNATURE WAS ABLE TO DISCRIMINATE REFRACTORY ANEMIAS WITH RING SIDEROBLASTS FROM REFRACTORY ANEMIAS WITH EXCESS OF BLASTS. BY COMPARING MRNAS FROM THESE TWO FORMS OF MYELODYSPLASTIC SYNDROMES WE DERIVED A SECOND GENE EXPRESSION SIGNATURE. THIS SIGNATURE SEPARATED THE MYELODYSPLASTIC AND MYELOPROLIFERATIVE FORMS OF CHRONIC MYELOMONOCYTIC LEUKEMIAS. THESE RESULTS WERE VALIDATED USING TWO INDEPENDENT GENE EXPRESSION DATA SETS. WE FOUND THAT MYELODYSPLASTIC CHRONIC MYELOMONOCYTIC LEUKEMIAS ARE CHARACTERIZED BY MUTATIONS IN TRANSCRIPTION/EPIGENETIC REGULATORS (ASXL1, RUNX1, TET2) AND SPLICING GENES (SRSF2) AND THE ABSENCE OF MUTATIONS IN SIGNALING GENES. MYELODYSPLASTIC CHRONIC MYELOMONOCYTIC LEUKEMIAS AND REFRACTORY ANEMIAS WITH RING SIDEROBLASTS SHARE A COMMON EXPRESSION PROGRAM SUGGESTING THEY ARE PART OF A CONTINUUM, WHICH IS NOT TOTALLY EXPLAINED BY THEIR SIMILAR BUT NOT, HOWEVER, IDENTICAL MUTATION SPECTRUM.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18   791  25 CELLULAR AND MOLECULAR NETWORKS IN CHRONIC MYELOID LEUKEMIA: THE LEUKEMIC STEM, PROGENITOR AND STROMAL CELL INTERPLAY. THE USE OF IMATINIB, SECOND AND THIRD GENERATION ABL TYROSINE KINASE INHIBITORS (TKI) (I.E. DASATINIB, NILOTINIB, BOSUTINIB AND PONATINIB) MADE CML A CLINICALLY MANAGEABLE AND, IN A SMALL PERCENTAGE OF CASES, A CURED DISEASE. TKI THERAPY ALSO TURNED CML BLASTIC TRANSFORMATION INTO A RARE EVENT; HOWEVER, DISEASE PROGRESSION STILL OCCURS IN THOSE PATIENTS WHO ARE REFRACTORY, NOT COMPLIANT WITH TKI THERAPY OR DEVELOP RESISTANCE TO MULTIPLE TKIS. IN THE PAST FEW YEARS, IT BECAME CLEAR THAT THE BCRABL1 ONCOGENE DOES NOT OPERATE ALONE TO DRIVE DISEASE EMERGENCE, MAINTENANCE AND PROGRESSION. INDEED, IT SEEMS THAT BONE MARROW (BM) MICROENVIRONMENT-GENERATED SIGNALS AND CELL AUTONOMOUS BCRABL1 KINASE-INDEPENDENT GENETIC AND EPIGENETIC ALTERATIONS ALL CONTRIBUTE TO: I. PERSISTENCE OF A QUIESCENT LEUKEMIC STEM CELL (LSC) RESERVOIR, II. INNATE OR ACQUIRED RESISTANCE TO TKIS, AND III. PROGRESSION INTO THE FATAL BLAST CRISIS STAGE. HEREIN, WE REVIEW THE INTRICATE LEUKEMIC NETWORK IN WHICH ABERRANT, BUT FINELY TUNED, SURVIVAL, MITOGENIC AND SELF-RENEWAL SIGNALS ARE GENERATED BY LEUKEMIC PROGENITORS, STROMAL CELLS, IMMUNE CELLS AND METABOLIC MICROENVIRONMENTAL CONDITIONS (E.G. HYPOXIA) TO PROMOTE LSC MAINTENANCE AND BLASTIC TRANSFORMATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
19  6574  27 TREATMENT OF CHRONIC MYELOMONOCYTIC LEUKEMIA WITH 5-AZACYTIDINE: CASE REPORTS. EPIGENETIC THERAPY WITH HYPOMETHYLATING AGENT (5-AZACYTIDINE; AZA) IS COMMON IN THE MANAGEMENT OF SPECIFIC SUBTYPES OF MYELODYSPLASTIC SYNDROME (MDS), BUT THERE ARE ONLY FEW STUDIES IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) PATIENTS. IN THIS PAPER OUR EXPERIENCE WITH 3 CMML PATIENTS TREATED WITH AZA IS DESCRIBED. IN ONE PATIENT TRANSFUSION INDEPENDENCY WAS OBSERVED AFTER 4 TREATMENT CYCLES; IN ONE CASE A PARTIAL RESPONSE WAS RECORDED, BUT A PROGRESSION TO ACUTE MYELOID LEUKEMIA (AML) AFTER 13 AZA CYCLES HAS APPEARED. IN ONE PATIENT, AZA IN REDUCED DOSAGE WAS ADMINISTERED AS A BRIDGING TREATMENT BEFORE ALLOGENEIC STEM CELL TRANSPLANTATION (ASCT), BUT IN THE CONTROL BONE MARROW ASPIRATE (BEFORE ASCT) A PROGRESSION TO AML WAS RECORDED. FUTURE STUDIES ARE MANDATORY FOR EVALUATION OF NEW MOLECULAR AND CLINICAL FEATURES WHICH COULD PREDICT THE EFFICIENCY OF HYPOMETHYLATING AGENTS IN CMML THERAPY WITH RESPECT TO OVERALL SURVIVAL, EVENT-FREE SURVIVAL, QUALITY-ADJUSTED LIFE YEAR, AND PHARMACOECONOMY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
20  5212  25 PRESERVATION OF QUIESCENT CHRONIC MYELOGENOUS LEUKEMIA STEM CELLS BY THE BONE MARROW MICROENVIRONMENT. THE MAJORITY OF LEUKEMIA PATIENTS ACHIEVING REMISSION ULTIMATELY RELAPSE. PERSISTENCE OF LEUKEMIA STEM CELLS (LSC) CAPABLE OF REGENERATING LEUKEMIA IS A MAJOR CAUSE OF RELAPSE. THERE IS A PRESSING NEED TO BETTER UNDERSTAND MECHANISMS OF LSC REGULATION AND THEIR RESISTANCE TO THERAPY IN ORDER TO IMPROVE OUTCOMES FOR LEUKEMIA. CHRONIC MYELOGENOUS LEUKEMIA (CML) IS A LETHAL MYELOPROLIFERATIVE DISORDER THAT THAT IS CAUSED BY HEMATOPOIETIC STEM CELL (HSC) TRANSFORMATION BY THE BCR-ABL TYROSINE KINASE. TREATMENT WITH TYROSINE KINASE INHIBITORS (TKI) HAS REVOLUTIONIZED CML TREATMENT, BUT FAILS TO ELIMINATE LSC RESPONSIBLE FOR PROPAGATING AND REGENERATING LEUKEMIA. THEREFORE, PATIENTS REQUIRE CONTINUED TREATMENT TO PREVENT RELAPSE. LEUKEMIC AND NORMAL STEM CELLS SHARE PROPERTIES OF QUIESCENCE AND SELF-RENEWAL, THAT ARE SUPPORTED BY BONE MARROW NICHES. PERSISTENCE OF LSC AFTER TKI TREATMENT IS RELATED TO TYROSINE KINASE INDEPENDENT MECHANISMS WHICH INCLUDE INTRINSIC PROPERTIES OF LSCS DETERMINED BY EPIGENETIC ALTERATIONS, ALTERED TRANSCRIPTIONAL REGULATORY NETWORKS OR MITOCHONDRIAL/METABOLIC CHANGES. IN ADDITION TO CELL INTRINSIC CHANGES, SIGNALS FROM THE BONE MARROW MICROENVIRONMENT (BMM) PLAY A CRITICAL ROLE IN PROTECTING LSC FROM TKI TREATMENT. EACH TYPE OF ALTERATION MAY OFFER POTENTIAL POINTS OF INTERVENTION FOR THERAPEUTIC TARGETING OF LSC.	2018