1 3158 149 GLYCOGEN SYNTHASE KINASE 3BETA MISSPLICING CONTRIBUTES TO LEUKEMIA STEM CELL GENERATION. RECENT EVIDENCE SUGGESTS THAT A RARE POPULATION OF SELF-RENEWING CANCER STEM CELLS (CSC) IS RESPONSIBLE FOR CANCER PROGRESSION AND THERAPEUTIC RESISTANCE. CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS AN IMPORTANT PARADIGM FOR UNDERSTANDING THE GENETIC AND EPIGENETIC EVENTS INVOLVED IN CSC PRODUCTION. CML PROGRESSES FROM A CHRONIC PHASE (CP) IN HEMATOPOIETIC STEM CELLS (HSC) THAT HARBOR THE BCR-ABL TRANSLOCATION, TO BLAST CRISIS (BC), CHARACTERIZED BY ABERRANT ACTIVATION OF BETA-CATENIN WITHIN GRANULOCYTE-MACROPHAGE PROGENITORS (GMP). A MAJOR BARRIER TO PREDICTING AND INHIBITING BLAST CRISIS TRANSFORMATION HAS BEEN THE IDENTIFICATION OF MECHANISMS DRIVING BETA-CATENIN ACTIVATION. HERE WE SHOW THAT BC CML MYELOID PROGENITORS, IN PARTICULAR GMP, SERIALLY TRANSPLANT LEUKEMIA IN IMMUNOCOMPROMISED MICE AND THUS ARE ENRICHED FOR LEUKEMIA STEM CELLS (LSC). NOTABLY, CDNA SEQUENCING OF WNT/BETA-CATENIN PATHWAY REGULATORY GENES, INCLUDING ADENOMATOUS POLYPOSIS COLI, GSK3BETA, AXIN 1, BETA-CATENIN, LYMPHOID ENHANCER FACTOR-1, CYCLIN D1, AND C-MYC, REVEALED A NOVEL IN-FRAME SPLICE DELETION OF THE GSK3BETA KINASE DOMAIN IN THE GMP OF BC SAMPLES THAT WAS NOT DETECTABLE BY SEQUENCING IN BLASTS OR NORMAL PROGENITORS. MOREOVER, BC CML PROGENITORS WITH MISSPLICED GSK3BETA HAVE ENHANCED BETA-CATENIN EXPRESSION AS WELL AS SERIAL ENGRAFTMENT POTENTIAL WHILE REINTRODUCTION OF FULL-LENGTH GSK3BETA REDUCES BOTH IN VITRO REPLATING AND LEUKEMIC ENGRAFTMENT. WE PROPOSE THAT CP CML IS INITIATED BY BCR-ABL EXPRESSION IN AN HSC CLONE BUT THAT PROGRESSION TO BC MAY INCLUDE MISSPLICING OF GSK3BETA IN GMP LSC, ENABLING UNPHOSPHORYLATED BETA-CATENIN TO PARTICIPATE IN LSC SELF-RENEWAL. MISSPLICING OF GSK3BETA REPRESENTS A UNIQUE MECHANISM FOR THE EMERGENCE OF BC CML LSC AND MIGHT PROVIDE A NOVEL DIAGNOSTIC AND THERAPEUTIC TARGET. 2009 2 572 44 BCR-ABL1 KINASE-DEPENDENT ALTERATION OF MRNA METABOLISM: POTENTIAL ALTERNATIVES FOR THERAPEUTIC INTERVENTION. THE USE OF FIRST- AND SECOND-GENERATION TYROSINE KINASE INHIBITORS (TKIS) SIGNIFICANTLY IMPROVES PROGNOSIS FOR PATIENTS WITH EARLY CHRONIC PHASE CHRONIC MYELOID LEUKEMIA (CML) AND EFFICIENTLY COUNTERACTS LEUKEMIA IN MOST PATIENTS WITH CML BEARING A DISEASE CHARACTERIZED BY THE EXPRESSION OF BCR-ABL1 MUTANTS. HOWEVER, THE SO-CALLED 'TINIB' TKIS (E.G. IMATINIB, NILOTINIB, DASATINIB, AND BOSUTINIB) ARE BOTH INEFFECTIVE IN PATIENTS WHO UNDERGO BLASTIC TRANSFORMATION AND UNABLE TO ERADICATE CML AT THE STEM CELL LEVEL. THIS RAISES A FEW IMPORTANT QUESTIONS. IS BCR-ABL1 EXPRESSION AND/OR ACTIVITY ESSENTIAL FOR BLASTIC TRANSFORMATION? IS BLASTIC TRANSFORMATION THE RESULT OF GENETIC OR EPIGENETIC EVENTS THAT OCCUR AT THE STEM CELL LEVEL WHICH ONLY BECOME APPARENT IN THE GRANULOCYTE-MACROPHAGE PROGENITOR (GMP) CELL POOL, OR DOES IT ARISE DIRECTLY AT THE GMP LEVEL? AS ALTERED MRNA METABOLISM CONTRIBUTES TO THE PHENOTYPE OF BLAST CRISIS CML PROGENITORS (DECREASED TRANSLATION OF TUMOR SUPPRESSOR GENES AND TRANSCRIPTION FACTORS ESSENTIAL FOR TERMINAL DIFFERENTIATION AND INCREASED TRANSLATION OF ANTI-APOPTOTIC GENES), ONE ATTRACTIVE CONCEPT IS TO RESTORE LEVELS OF THESE ESSENTIAL MOLECULES TO THEIR NORMAL LEVELS. IN THIS REVIEW, WE DISCUSS THE MECHANISMS BY WHICH MRNA PROCESSING, TRANSLATION, AND DEGRADATION ARE DEREGULATED IN BCR-ABL1 MYELOID BLAST CRISIS CML PROGENITORS, AND PRESENT ENCOURAGING RESULTS FROM STUDIES WITH PHARMACOLOGIC INHIBITORS WHICH SUPPORT THEIR INCLUSION IN THE CLINIC. 2011 3 4388 53 MLL2/KMT2D AND MLL3/KMT2C EXPRESSION CORRELATES WITH DISEASE PROGRESSION AND RESPONSE TO IMATINIB MESYLATE IN CHRONIC MYELOID LEUKEMIA. BACKGROUND: CHRONIC MYELOID LEUKEMIA (CML) IS A CLONAL MYELOPROLIFERATIVE NEOPLASM WHOSE PATHOGENESIS IS LINKED TO THE PHILADELPHIA CHROMOSOME PRESENCE THAT GENERATES THE BCR-ABL1 FUSION ONCOGENE. TYROSINE KINASE INHIBITORS (TKI) SUCH AS IMATINIB MESYLATE (IM) DRAMATICALLY IMPROVED THE TREATMENT EFFICIENCY AND SURVIVAL OF CML PATIENTS BY TARGETING BCR-ABL TYROSINE KINASE. THE DISEASE SHOWS THREE DISTINCT CLINICAL-LABORATORY STAGES: CHRONIC PHASE, ACCELERATED PHASE AND BLAST CRISIS. ALTHOUGH PATIENTS IN THE CHRONIC PHASE RESPOND WELL TO TREATMENT, PATIENTS IN THE ACCELERATED PHASE OR BLAST CRISIS USUALLY SHOW THERAPY RESISTANCE AND CML RELAPSE. IT IS CRUCIAL, THEREFORE, TO IDENTIFY BIOMARKERS TO PREDICT CML GENETIC EVOLUTION AND RESISTANCE TO TKI THERAPY, CONSIDERING NOT ONLY THE EFFECTS OF GENETIC ABERRATIONS BUT ALSO THE ROLE OF EPIGENETIC ALTERATIONS DURING THE DISEASE. ALTHOUGH DYSREGULATIONS IN EPIGENETIC MODULATORS SUCH AS HISTONE METHYLTRASNFERASES HAVE ALREADY BEEN DESCRIBED FOR SOME HEMATOLOGIC MALIGNANCIES, TO DATE VERY LIMITED DATA IS AVAILABLE FOR CML, ESPECIALLY WHEN CONSIDERING THE LYSINE METHYLTRANSFERASE MLL2/KMT2D AND MLL3/KMT2C. METHODS: HERE WE INVESTIGATED THE EXPRESSION PROFILE OF BOTH GENES IN CML PATIENTS IN DIFFERENT STAGES OF THE DISEASE, IN PATIENTS SHOWING DIFFERENT RESPONSES TO THERAPY WITH IM AND IN NON-NEOPLASTIC CONTROL SAMPLES. IMATINIB SENSITIVE AND RESISTANT CML CELL LINES WERE ALSO USED TO INVESTIGATE WHETHER TREATMENT WITH OTHER TYROSINE KINASE INHIBITORS INTERFERED IN THEIR EXPRESSION. RESULTS: IN PATIENTS, BOTH METHYLTRANSFERASES WERE EITHER UPREGULATED OR WITH BASAL EXPRESSION LEVEL DURING THE CHRONIC PHASE COMPARED TO CONTROLS. INTERESTINGLY, MLL3/KMT2C AND SPECIALLY MLL2/KMT2D LEVELS DECREASED DURING DISEASE PROGRESSION CORRELATING WITH DISTINCT CLINICAL STAGES. FURTHERMORE, MLL2/KMT2D WAS DECREASED IN PATIENTS RESISTANT TO IM TREATMENT. A RESCUE IN THE EXPRESSION OF BOTH MLL GENES WAS OBSERVED IN KCL22S, A CML CELL LINE SENSITIVE TO IM, AFTER TREATMENT WITH DASATINIB OR NILOTINIB WHICH WAS ASSOCIATED WITH A HIGHER RATE OF APOPTOSIS, AN ENHANCED EXPRESSION OF P21 (CDKN1A) AND A CONCOMITANT DECREASE IN THE EXPRESSION OF CDK2, CDK4 AND CYCLIN B1 (CCNB1) IN COMPARISON TO UNTREATED KCL22S CONTROL OR IM RESISTANT KCL22R CELL LINE, WHICH SUGGESTS INVOLVEMENT OF P53 REGULATED PATHWAY. CONCLUSION: OUR RESULTS ESTABLISHED A NEW ASSOCIATION BETWEEN MLL2/KMT2D AND MLL3/KMT2C GENES WITH CML AND SUGGEST THAT MLL2/KMT2D IS ASSOCIATED WITH DISEASE EVOLUTION AND MAY BE A POTENTIAL MARKER TO PREDICT THE DEVELOPMENT OF THERAPY RESISTANCE. 2018 4 952 48 CHRONIC MYELOID LEUKEMIA STEM CELL BIOLOGY. LEUKEMIA PROGRESSION AND RELAPSE IS FUELED BY LEUKEMIA STEM CELLS (LSC) THAT ARE RESISTANT TO CURRENT TREATMENTS. IN THE PROGRESSION OF CHRONIC MYELOID LEUKEMIA (CML), BLAST CRISIS PROGENITORS ARE CAPABLE OF ADOPTING MORE PRIMITIVE BUT DEREGULATED STEM CELL FEATURES WITH ACQUIRED RESISTANCE TO TARGETED THERAPIES. THIS IN TURN PROMOTES LSC BEHAVIOR CHARACTERIZED BY ABERRANT SELF-RENEWAL, DIFFERENTIATION, AND SURVIVAL CAPACITY. MULTIPLE REPORTS SUGGEST THAT CELL CYCLE ALTERATIONS, ACTIVATION OF CRITICAL SIGNALING PATHWAYS, ABERRANT MICROENVIRONMENTAL CUES FROM THE HEMATOPOIETIC NICHE, AND ABERRANT EPIGENETIC EVENTS AND DEREGULATION OF RNA PROCESSING MAY FACILITATE THE ENHANCED SURVIVAL AND MALIGNANT TRANSFORMATION OF CML PROGENITORS. HERE WE REVIEW THE MOLECULAR EVOLUTION OF CML LSC THAT PROMOTES CML PROGRESSION AND RELAPSE. RECENT ADVANCES IN THESE AREAS HAVE IDENTIFIED NOVEL TARGETS THAT REPRESENT IMPORTANT AVENUES FOR FUTURE THERAPEUTIC APPROACHES AIMED AT SELECTIVELY ERADICATING THE LSC POPULATION WHILE SPARING NORMAL HEMATOPOIETIC PROGENITORS IN PATIENTS SUFFERING FROM CHRONIC MYELOID MALIGNANCIES. 2012 5 4741 45 NOVEL HDAC INHIBITOR MAKV-8 AND IMATINIB SYNERGISTICALLY KILL CHRONIC MYELOID LEUKEMIA CELLS VIA INHIBITION OF BCR-ABL/MYC-SIGNALING: EFFECT ON IMATINIB RESISTANCE AND STEM CELLS. BACKGROUND: CHRONIC MYELOID LEUKEMIA (CML) PATHOGENESIS IS MAINLY DRIVEN BY THE ONCOGENIC BREAKPOINT CLUSTER REGION-ABELSON MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1 (BCR-ABL) FUSION PROTEIN. SINCE BCR-ABL DISPLAYS ABNORMAL CONSTITUTIVE TYROSINE KINASE ACTIVITY, THERAPIES USING TYROSINE KINASE INHIBITORS (TKIS) SUCH AS IMATINIB REPRESENT A MAJOR BREAKTHROUGH FOR THE OUTCOME OF CML PATIENTS. NEVERTHELESS, THE DEVELOPMENT OF TKI RESISTANCE AND THE PERSISTENCE OF LEUKEMIA STEM CELLS (LSCS) REMAIN BARRIERS TO CURE THE DISEASE, JUSTIFYING THE DEVELOPMENT OF NOVEL THERAPEUTIC APPROACHES. SINCE THE ACTIVITY OF HISTONE DEACETYLASE (HDAC) IS DEREGULATED IN NUMEROUS CANCERS INCLUDING CML, PAN-HDAC INHIBITORS MAY REPRESENT PROMISING THERAPEUTIC REGIMENS FOR THE TREATMENT OF CML CELLS IN COMBINATION WITH TKI. RESULTS: WE ASSESSED THE ANTI-LEUKEMIC ACTIVITY OF A NOVEL HYDROXAMATE-BASED PAN-HDAC INHIBITOR MAKV-8, WHICH COMPLIED WITH THE LIPINSKI'S "RULE OF FIVE," IN VARIOUS CML CELLS ALONE OR IN COMBINATION WITH IMATINIB. WE VALIDATED THE IN VITRO HDAC-INHIBITORY POTENTIAL OF MAKV-8 AND DEMONSTRATED EFFICIENT BINDING TO THE LIGAND-BINDING POCKET OF HDAC ISOENZYMES. IN CELLULO, MAKV-8 SIGNIFICANTLY INDUCED TARGET PROTEIN ACETYLATION, DISPLAYED CYTOSTATIC AND CYTOTOXIC PROPERTIES, AND TRIGGERED CONCOMITANT ER STRESS/PROTECTIVE AUTOPHAGY LEADING TO CANONICAL CASPASE-DEPENDENT APOPTOSIS. CONSIDERING THE SPECIFIC UPREGULATION OF SELECTED HDACS IN LSCS FROM CML PATIENTS, WE INVESTIGATED THE DIFFERENTIAL TOXICITY OF A CO-TREATMENT WITH MAKV-8 AND IMATINIB IN CML VERSUS HEALTHY CELLS. WE ALSO SHOWED THAT BECLIN-1 KNOCKDOWN PREVENTED MAKV-8-IMATINIB COMBINATION-INDUCED APOPTOSIS. MOREOVER, MAKV-8 AND IMATINIB CO-TREATMENT SYNERGISTICALLY REDUCED BCR-ABL-RELATED SIGNALING PATHWAYS INVOLVED IN CML CELL GROWTH AND SURVIVAL. SINCE OUR RESULTS SHOWED THAT LSCS FROM CML PATIENTS OVEREXPRESSED C-MYC, IMPORTANTLY MAKV-8-IMATINIB CO-TREATMENT REDUCED C-MYC LEVELS AND THE LSC POPULATION. IN VIVO, TUMOR GROWTH OF XENOGRAFTED K-562 CELLS IN ZEBRAFISH WAS COMPLETELY ABROGATED UPON COMBINED TREATMENT WITH MAKV-8 AND IMATINIB. CONCLUSIONS: COLLECTIVELY, THE PRESENT FINDINGS SHOW THAT COMBINATIONS HDAC INHIBITOR-IMATINIB ARE LIKELY TO OVERCOME DRUG RESISTANCE IN CML PATHOLOGY. 2020 6 571 37 BCR-ABL INDUCES AUTOCRINE IGF-1 SIGNALING. BCR-ABL ONCOGENE IS RESPONSIBLE FOR THE INITIAL PHASE OF CHRONIC MYELOGENOUS LEUKEMIA (CML), WHICH IS EFFECTIVELY TREATED BY THE BCR-ABL INHIBITOR IMATINIB. OVER TIME PATIENTS BECOME RESISTANT TO TREATMENT AND PROGRESS TO BLAST CRISIS, AN EVENT THAT IS DRIVEN BY ADDITIONAL GENETIC AND EPIGENETIC ABERRATIONS. RECENTLY, WE SHOWED THAT RIZ1 EXPRESSION DECREASES IN BLAST CRISIS AND THAT RE-EXPRESSION OF RIZ1 INHIBITS IGF-1 EXPRESSION. IGF-1 SIGNALING IS REQUIRED IN MANY STAGES OF HEMATOPOIESIS AND INAPPROPRIATE ACTIVATION OF AUTOCRINE IGF-1 SIGNALING MAY FACILITATE TRANSFORMATION TO BLAST CRISIS. WE OBSERVED THAT IN 8 OUT OF 11 MATCHED CML PATIENT BIOPSIES THE IGF-1 EXPRESSION IS ELEVATED IN BLAST CRISIS. WE EXAMINED MECHANISMS USED BY CML BLAST CRISIS CELL LINES TO ACTIVATE IGF-1 EXPRESSION. WE FOUND THAT BCR-ABL ACTIVATES AUTOCRINE IGF-1 SIGNALING USING HCK AND STAT5B. INHIBITION OF THESE SIGNALING COMPONENTS USING SMALL MOLECULE DRUGS OR SHRNA DECREASES PROLIFERATION AND ENHANCES APOPTOSIS. TOGETHER, OUR STUDY SUGGESTS THAT ABERRANT IGF-1 SIGNALING IS AN IMPORTANT EVENT IN BLAST CRISIS TRANSFORMATION AND IT PROVIDES A MECHANISM TO EXPLAIN THE ACTIVITY OF IGF-1R AND HCK INHIBITORS IN BLOCKING CML BLAST CRISIS PHENOTYPES. 2008 7 3234 33 HEMATOPOIETIC AND CHRONIC MYELOID LEUKEMIA STEM CELLS: MULTI-STABILITY VERSUS LINEAGE RESTRICTION. THERE IS COMPELLING EVIDENCE TO SUPPORT THE VIEW THAT THE CELL-OF-ORIGIN FOR CHRONIC MYELOID LEUKEMIA IS A HEMATOPOIETIC STEM CELL. UNLIKE NORMAL HEMATOPOIETIC STEM CELLS, THE PROGENY OF THE LEUKEMIA STEM CELLS ARE PREDOMINANTLY NEUTROPHILS DURING THE DISEASE CHRONIC PHASE AND THERE IS A MILD ANEMIA. THE HALLMARK ONCOGENE FOR CHRONIC MYELOID LEUKEMIA IS THE BCR-ABLP210 FUSION GENE. VARIOUS STUDIES HAVE EXCLUDED A ROLE FOR BCR-ABLP210 EXPRESSION IN MAINTAINING THE POPULATION OF LEUKEMIA STEM CELLS. STUDIES OF BCR-ABLP210 EXPRESSION IN EMBRYONAL STEM CELLS THAT WERE DIFFERENTIATED INTO HEMATOPOIETIC STEM CELLS AND OF THE EXPRESSION IN TRANSGENIC MICE HAVE REVEALED THAT BCR-ABLP210 IS ABLE TO VEER HEMATOPOIETIC STEM AND PROGENITOR CELLS TOWARDS A MYELOID FATE. FOR THE TRANSGENIC MICE, GLOBAL CHANGES TO THE EPIGENETIC LANDSCAPE WERE OBSERVED. IN CHRONIC MYELOID LEUKEMIA, THE ABILITY OF THE LEUKEMIA STEM CELLS TO CHOOSE FROM THE MANY FATES THAT ARE AVAILABLE TO NORMAL HEMATOPOIETIC STEM CELLS APPEARS TO BE DEREGULATED BY BCR-ABLP210 AND CHANGES TO THE EPIGENOME ARE ALSO IMPORTANT. EVEN SO, WE STILL DO NOT HAVE A PRECISE PICTURE AS TO WHY NEUTROPHILS ARE ABUNDANTLY PRODUCED IN CHRONIC MYELOID LEUKEMIA. 2022 8 1465 36 DISSECTING THE ROLE OF ABERRANT DNA METHYLATION IN HUMAN LEUKAEMIA. CHRONIC MYELOID LEUKAEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY THE GENETIC TRANSLOCATION T(9;22)(Q34;Q11.2) ENCODING FOR THE BCR-ABL FUSION ONCOGENE. HOWEVER, MANY MOLECULAR MECHANISMS OF THE DISEASE PROGRESSION STILL REMAIN POORLY UNDERSTOOD. A GROWING BODY OF EVIDENCE SUGGESTS THAT THE EPIGENETIC ABNORMALITIES ARE INVOLVED IN TYROSINE KINASE RESISTANCE IN CML, LEADING TO LEUKAEMIC CLONE ESCAPE AND DISEASE PROPAGATION. HERE WE SHOW THAT, BY APPLYING CELLULAR REPROGRAMMING TO PRIMARY CML CELLS, ABERRANT DNA METHYLATION CONTRIBUTES TO THE DISEASE EVOLUTION. IMPORTANTLY, USING A BCR-ABL INDUCIBLE MURINE MODEL, WE DEMONSTRATE THAT A SINGLE ONCOGENIC LESION TRIGGERS DNA METHYLATION CHANGES, WHICH IN TURN ACT AS A PRECIPITATING EVENT IN LEUKAEMIA PROGRESSION. 2015 9 2971 29 GENETIC AND EPIGENETIC SILENCING OF MICRORNA-203 ENHANCES ABL1 AND BCR-ABL1 ONCOGENE EXPRESSION. THE MAMMALIAN GENOME CONTAINS SEVERAL HUNDRED MICRORNAS THAT REGULATE GENE EXPRESSION THROUGH MODULATION OF TARGET MRNAS. HERE, WE REPORT A FRAGILE CHROMOSOMAL REGION LOST IN SPECIFIC HEMATOPOIETIC MALIGNANCIES. THIS 7 MB REGION ENCODES ABOUT 12% OF ALL GENOMIC MICRORNAS, INCLUDING MIR-203. THIS MICRORNA IS ADDITIONALLY HYPERMETHYLATED IN SEVERAL HEMATOPOIETIC TUMORS, INCLUDING CHRONIC MYELOGENOUS LEUKEMIAS AND SOME ACUTE LYMPHOBLASTIC LEUKEMIAS. A PUTATIVE MIR-203 TARGET, ABL1, IS SPECIFICALLY ACTIVATED IN THESE HEMATOPOIETIC MALIGNANCIES IN SOME CASES AS A BCR-ABL1 FUSION PROTEIN (PHILADELPHIA CHROMOSOME). RE-EXPRESSION OF MIR-203 REDUCES ABL1 AND BCR-ABL1 FUSION PROTEIN LEVELS AND INHIBITS TUMOR CELL PROLIFERATION IN AN ABL1-DEPENDENT MANNER. THUS, MIR-203 FUNCTIONS AS A TUMOR SUPPRESSOR, AND RE-EXPRESSION OF THIS MICRORNA MIGHT HAVE THERAPEUTIC BENEFITS IN SPECIFIC HEMATOPOIETIC MALIGNANCIES. 2008 10 3532 37 IMATINIB INDEPENDENT ABERRANT METHYLATION OF NOV/CCN3 IN CHRONIC MYELOGENOUS LEUKEMIA PATIENTS: A MECHANISM UPSTREAM OF BCR-ABL1 FUNCTION? BACKGROUND: THE NOV GENE PRODUCT, CCN3, HAS BEEN REPORTED IN A DIVERSE RANGE OF TUMORS TO SERVE AS A NEGATIVE GROWTH REGULATOR, WHILE ACTING AS A TUMOR SUPPRESSOR IN CHRONIC MYELOGENOUS LEUKEMIA (CML). HOWEVER, THE PRECISE MECHANISM OF ITS SILENCING IN CML IS POORLY UNDERSTOOD. IN THE CURRENT STUDY, WE AIMED TO QUERY IF THE GENE REGULATION OF CCN3 IS MEDIATED BY THE PROMOTER METHYLATION IN THE PATIENTS WITH CML. IN ADDITION, TO CLARIFY WHETHER THE EPIGENETIC SILENCING IS AFFECTED BY BCR-ABL1 INHIBITION, WE ASSESSED THE METHYLATION STATUS IN THE PATIENTS AT DIFFERENT TIME INTERVALS FOLLOWING THE TYROSINE KINASE INHIBITION USING IMATINIB THERAPY, AS THE FIRST-LINE TREATMENT FOR THIS TYPE OF LEUKEMIA. METHODS: TO ADDRESS THIS ISSUE, WE APPLIED BISULFITE-SEQUENCING TECHNIQUE AS A HIGH-RESOLUTION METHOD TO STUDY THE REGULATORY SEGMENT OF THE CCN3 GENE. THE RESULTS WERE ANALYZED IN NEWLY DIAGNOSED CML PATIENTS AS WELL AS FOLLOWING IMATINIB THERAPY. WE ALSO EVALUATED THE CORRELATION OF CCN3 PROMOTER METHYLATION WITH BCR-ABL1 LEVELS. RESULTS: OUR FINDINGS REVEALED THAT THE METHYLATION OCCURS FREQUENTLY IN THE PROMOTER REGION OF CML PATIENTS SHOWING A SIGNIFICANT INCREASE OF THE METHYLATED PERCENTAGE AT THE CPG SITES COMPARED TO NORMAL INDIVIDUALS. INTERESTINGLY, THIS HYPERMETHYLATION WAS INDICATED TO BE INDEPENDENT OF BCR-ABL1 TITERS IN BOTH GROUPS, WHICH MIGHT SUGGEST A MECHANISM BEYOND THE BCR-ABL1 FUNCTION. CONCLUSION: DESPITE SUGGESTING THAT THE CCN3 HYPERMETHYLATION ACTS AS A MOLECULAR MECHANISM INDEPENDENT OF BCR-ABL1 FUNCTION IN CML PATIENTS, THIS SCENARIO REQUIRES FURTHER VALIDATION BY COMPLEMENTARY EXPERIMENTS. IN THE CASE OF ACTING UPSTREAM OF BCR-ABL1 SIGNALING, THE METHYLATION MARKER CAN PROVIDE EARLY DETECTION AND A NOVEL PLATFORM FOR TARGETED EPIGENETIC MODIFIERS FOR EFFICIENT TREATMENT IN IMATINIB RESISTANT PATIENTS. 2019 11 5212 42 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 12 1860 48 EMBRYONIC PROGRAM ACTIVATED DURING BLAST CRISIS OF CHRONIC MYELOGENOUS LEUKEMIA (CML) IMPLICATES A TCF7L2 AND MYC COOPERATIVE CHROMATIN BINDING. CHRONIC MYELOID LEUKEMIA (CML) IS CHARACTERIZED BY AN INHERENT GENETIC INSTABILITY, WHICH CONTRIBUTES TO THE PROGRESSION OF THE DISEASE TOWARDS AN ACCELERATED PHASE (AP) AND BLAST CRISIS (BC). SEVERAL CYTOGENETIC AND GENOMIC ALTERATIONS HAVE BEEN REPORTED IN THE PROGRESSION TOWARDS BC, BUT THE PRECISE MOLECULAR MECHANISMS OF THIS EVENT ARE UNDETERMINED. TRANSCRIPTION FACTOR 7 LIKE 2 (TFC7L2) IS A MEMBER OF THE TCF FAMILY OF PROTEINS THAT ARE KNOWN TO ACTIVATE WNT TARGET GENES SUCH AS CYCLIN D1. TCF7L2 HAS BEEN SHOWN TO BE OVEREXPRESSED IN ACUTE MYELOID LEUKEMIA (AML) AND REPRESENTS A DRUGGABLE TARGET. WE REPORT HERE THAT TCF7L2 TRANSCRIPTION FACTOR EXPRESSION WAS FOUND TO BE CORRELATED TO BLAST CELL NUMBERS DURING THE PROGRESSION OF THE DISEASE. IN THESE CELLS, TCF7L2 CHIP-SEQUENCING HIGHLIGHTED DISTAL CIS ACTIVE ENHANCER, SUCH AS ELEMENTS IN SMAD3, ATF5, AND PRMT1 GENOMIC REGIONS AND A PROXIMAL ACTIVE TRANSCRIPTIONAL PROGRAM OF 144 GENES. THE ANALYSIS OF CHIP-SEQUENCING OF MYC REVEALED A SIGNIFICANT OVERLAPPING OF TCF7L2 EPIGENETIC PROGRAM WITH MYC. THE BETA-CATENIN ACTIVATOR LITHIUM CHLORIDE AND THE MYC-MAX DIMERIZATION INHIBITOR 10058-F4 SIGNIFICANTLY MODIFIED THE EXPRESSION OF THREE EPIGENETIC TARGETS IN THE BC CELL LINE K562. THESE RESULTS SUGGEST FOR THE FIRST TIME THE COOPERATIVE ROLE OF TCF7L2 AND MYC DURING CML-BC AND THEY STRENGTHEN PREVIOUS DATA SHOWING A POSSIBLE INVOLVEMENT OF EMBRYONIC GENES IN THIS PROCESS. 2020 13 5549 24 ROLE OF EPIGENETICS IN CHRONIC MYELOID LEUKEMIA. THE EFFICACY OF THERAPEUTIC MODALITIES IN CHRONIC MYELOID LEUKEMIA (CML) DEPENDS ON BOTH GENETIC AND EPIGENETIC MECHANISMS. THIS REVIEW FOCUSES ON EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF CML AND IN RESISTANCE OF TUMOR CELLS TO TYROSINE KINASE INHIBITORS LEADING TO THE LEUKEMIC CLONE ESCAPE AND PROPAGATION. REGULATORY EVENTS AT THE LEVELS OF GENE REGULATION BY TRANSCRIPTION FACTORS AND MICRORNAS ARE DISCUSSED IN THE CONTEXT OF CML PATHOGENESIS AND THERAPEUTIC MODALITIES. 2013 14 1142 39 CONCISE REVIEW: CHRONIC MYELOID LEUKEMIA: STEM CELL NICHE AND RESPONSE TO PHARMACOLOGIC TREATMENT. NOWADAYS, MORE THAN 90% OF PATIENTS AFFECTED BY CHRONIC MYELOID LEUKEMIA (CML) SURVIVE WITH A GOOD QUALITY OF LIFE, THANKS TO THE CLINICAL EFFICACY OF TYROSINE KINASE INHIBITORS (TKIS). NEVERTHELESS, POINT MUTATIONS OF THE ABL1 POCKET OCCURRING DURING TREATMENT MAY REDUCE BINDING OF TKIS, BEING RESPONSIBLE OF ABOUT 20% OF CASES OF RESISTANCE AMONG CML PATIENTS. IN ADDITION, THE PRESENCE OF LEUKEMIC STEM CELLS (LSCS) REPRESENTS THE MOST IMPORTANT EVENT IN LEUKEMIA PROGRESSION RELATED TO TKI RESISTANCE. LSCS EXPRESS STEM CELL MARKERS, INCLUDING ACTIVE EFFLUX PUMPS AND GENETIC AND EPIGENETIC ALTERATIONS TOGETHER WITH DEREGULATED CELL SIGNALING PATHWAYS INVOLVED IN SELF-RENEWAL, SUCH AS WNT/BETA-CATENIN, NOTCH, AND HEDGEHOG. MOREOVER, THE INTERACTION WITH THE BONE MARROW MICROENVIRONMENT, ALSO KNOWN AS HEMATOPOIETIC NICHE, MAY INFLUENCE THE PHENOTYPE OF SURROUNDING CELLS, WHICH EVADE MECHANISMS CONTROLLING CELL PROLIFERATION AND ARE LESS SENSITIVE OR FRANKLY RESISTANT TO TKIS. THIS REVIEW FOCUSES ON THE ROLE OF LSCS AND STEM CELL NICHE IN RELATION TO RESPONSE TO PHARMACOLOGICAL TREATMENTS. A LITERATURE SEARCH FROM PUBMED DATABASE WAS PERFORMED UNTIL APRIL 30, 2017, AND IT HAS BEEN ANALYZED ACCORDING TO KEYWORDS SUCH AS CHRONIC MYELOID LEUKEMIA, STEM CELL, LEUKEMIC STEM CELLS, HEMATOPOIETIC NICHE, TYROSINE KINASE INHIBITORS, AND DRUG RESISTANCE. STEM CELLS TRANSLATIONAL MEDICINE 2018;7:305-314. 2018 15 3352 32 HISTONE DEMETHYLASE RBP2 MEDIATES THE BLAST CRISIS OF CHRONIC MYELOID LEUKEMIA THROUGH AN RBP2/PTEN/BCR-ABL CASCADE. EPIGENETIC DISORDERS PLAY A KEY ROLE IN TUMORIGENESIS AND DEVELOPMENT, AMONG WHICH HISTONE METHYLATION ABNORMALITIES ARE COMMON. WHILE PATIENTS LIVING WITH CHRONIC MYELOID LEUKEMIA IN THE CHRONIC PHASE (CML-CP) HAVE A GOOD RESPONSE TO TKI, BLASTIC PHASE (CML-BP) PATIENTS DEMONSTRATE POOR EFFICACY AND HIGH FATALITY RATES. HOWEVER, WHILE THE MECHANISM OF BLAST CRISIS OF CHRONIC MYELOID LEUKEMIA REMAINS UNCLEAR, HIGH EXPRESSION AND ACTIVATION OF BCR-ABL ARE USUALLY RELATED TO CML BLAST CRISIS TRANSITION. WE FOUND THAT HISTONE H3 LYSINE 4 (H3K4) DEMETHYLASE RBP2 EXPRESSION IS NEGATIVELY CORRELATED WITH BCR-ABL EXPRESSION, WHICH SUGGESTS A REGULATORY LINK BETWEEN THESE TWO GENES. WE ALSO DISCOVERED THAT RBP2 MEDIATES THE DEPHOSPHORYLATION OF BCR-ABL BY DIRECTLY DOWNREGULATING PTEN EXPRESSION, DEPENDING ON HISTONE DEMETHYLASE ACTIVITY, WHILE PTEN TARGETS PROTEIN PHOSPHATASE ACTIVITY OF BCR-ABL, A PHOSPHATASE WHICH DIRECTLY DEPHOSPHORYLATES BCR-ABL. IN CLINICAL SPECIMENS, THE MRNA EXPRESSION OF RBP2 WAS FOUND TO BE POSITIVELY CORRELATED WITH THAT OF PTEN. THESE DATA SUGGEST THAT THE UNDER-EXPRESSION OF RBP2 PROMOTES BLAST CRISIS TRANSITION BY ACTIVATING AN RBP2/PTEN/BCR-ABL CASCADE. 2019 16 5669 28 SFRP1 PROMOTER METHYLATION IS ASSOCIATED WITH PERSISTENT PHILADELPHIA CHROMOSOME IN CHRONIC MYELOID LEUKEMIA. EPIGENETIC SILENCING OF SFRP GENES HAS BEEN SHOWN TO LEAD TO CONSTITUTIVE ACTIVATION OF THE CANONICAL WNT-SIGNALING PATHWAY. THE FIRST DESCRIPTION OF DEREGULATED WNT-SIGNALING ACTIVATION IN A HEMATOLOGICAL MALIGNANCY WAS REPORTED IN CHRONIC MYELOID LEUKEMIA (CML). TO INVESTIGATE WHETHER EPIGENETIC SILENCING OF SFRP IS RESPONSIBLE FOR THE OBSERVED WNT ACTIVATION IN CML, WE STUDIED THE METHYLATION AND MUTATIONAL STATUS OF THE SFRP1 PROMOTER IN 48 CHRONIC PHASE CML PATIENTS. OF THE 48 CML PATIENTS 41 WERE SHOWN TO BE UNMETHYLATED, 6 PATIENTS HEMI-METHYLATED AND 1 PATIENT FULLY METHYLATED AT THE SFRP1 PROMOTER. ALBEIT OBSERVED INFREQUENTLY IN CHRONIC PHASE CML, SFRP1 PROMOTER METHYLATION CORRELATED WITH PRIMARY CYTOGENETIC RESISTANCE TO IMATINIB MESYLATE. SFRP1 PROMOTER METHYLATION MAY INDICATE A GENETICALLY MORE UNSTABLE FORM OF DISEASE RESISTANT TO THERAPY AND PROVIDE A KEY BIOLOGICAL DIFFERENCE IN THERAPY RESISTANT PATIENTS, IN ADDITION TO A POSSIBLE MECHANISM FOR THE OBSERVED ACTIVATION OF CANONICAL WNT SIGNALING IN CML. 2009 17 4877 42 OVEREXPRESSION OF MIR-4433 BY SUBEROYLANILIDE HYDROXAMIC ACID SUPPRESSES GROWTH OF CML CELLS AND INDUCES APOPTOSIS THROUGH TARGETING BCR-ABL. BACKGROUND: TARGETING BCR-ABL IS THE KEY FOR THE TREATMENT OF CML. ALTHOUGH GREAT PROGRESS HAS BEEN ACHIEVED FOR THE TREATMENT OF CML PATIENTS IN CHRONIC STAGE, EFFECTIVE DRUGS WITH GOOD SAFETY ARE NOT AVAILABLE FOR THOSE IN ADVANCED STAGES OF CML PATIENTS. IN PRESENT STUDY, A HISTONE DEACETYLASE INHIBITOR, SUBEROYLANILIDE HYDROXAMIC ACID (SAHA), WAS USED TO SCREEN FOR MICRORNA THAT CAN TARGET BCR-ABL. METHODS: RT-QPCR WAS USED TO DETERMINE BCR-ABL AND MIR-4433 TRANSCRIPTION LEVEL IN CML CELLS. IN CML CELLS, PROTEINS INCLUDING PARP, CASPASE-3, ACETYL-HISTONE 3, HISTONE 3 AND BCR-ABL, AS WELL AS BCR-ABL DOWNSTREAM PROTEINS WERE DETECTED USING WESTERN BLOT. CELL VIABILITY AND APOPTOSIS WERE MONITORED RESPECTIVELY BY MTS ASSAY AND FLOW CYTOMETRY. THE CORRELATION BETWEEN MIR-4433 AND BCR-ABL WAS DETERMINED BY LUCIFERASE REPORTER ASSAY. THE ANTI-TUMOR EFFECT OF MIR-4433 TO K562 CELLS WAS EVALUATED BY NUDE MOUSE XENOGRAFT MODEL IN VIVO. RESULTS: SAHA UP-REGULATED THE ACETYLATION LEVEL OF HISTONE 3, AND EFFECTIVELY INHIBITED BCR-ABL MRNA LEVEL AND ITS DOWNSTREAM SIGNAL TRANSDUCTION PATHWAY, WHILE INHIBITING THE GROWTH OF CML CELLS AND INDUCING APOPTOSIS. FURTHERMORE, BIOINFORMATICS TOOLS PREDICTED THAT MIR-4433 IS A PUTATIVE MICRORNA TARGETING BCR-ABL AND THAT THE EXPRESSION LEVEL OF MIR-4433 WAS SIGNIFICANTLY INCREASED AFTER SAHA TREATMENT IN K562 CELLS. LUCIFERASE ACTIVITY ANALYSIS REVEALED THAT MIR-4433 DIRECTLY TARGETS BCR-ABL. ADDITIONALLY, TRANSIENT EXPRESSION OF MIR-4433 ABROGATED BCR-ABL ACTIVITY AND ITS DOWNSTREAM SIGNALING PATHWAYS WHILE INDUCING APOPTOSIS IN K562 CELLS. MOREOVER, STABLE EXPRESSION OF MIR-4433 SUPPRESSED BCR-ABL AND ITS DOWNSTREAM SIGNALING PATHWAY, AND INHIBITED THE GROWTH OF K562 CELLS IN VITRO AND THE GROWTH OF K562-XENOGRAFTS IN NUDE MICE. CONCLUSION: MIR-4433 WAS IDENTIFIED AS A MICRORNA TARGETING BCR-ABL, WHICH MAY BE SUBJECT TO EPIGENETIC REGULATION OF SAHA, A HISTONE DEACETYLASE INHIBITOR THAT HAS BEEN APPROVED BY THE US FDA FOR THE TREATMENT OF CUTANEOUS T-CELL LYMPHOMA. THE FINDINGS OF THIS STUDY PROVIDE A MOLECULAR BASIS FROM ANOTHER ANGLE FOR THE USE OF SAHA IN THE TREATMENT OF CML. 2019 18 5405 40 REGULATED EXPRESSION OF P210 BCR-ABL DURING EMBRYONIC STEM CELL DIFFERENTIATION STIMULATES MULTIPOTENTIAL PROGENITOR EXPANSION AND MYELOID CELL FATE. P210 BCR-ABL IS AN ACTIVATED TYROSINE KINASE ONCOGENE ENCODED BY THE PHILADELPHIA CHROMOSOME ASSOCIATED WITH HUMAN CHRONIC MYELOGENOUS LEUKEMIA (CML). THE DISEASE REPRESENTS A CLONAL DISORDER ARISING IN THE PLURIPOTENT HEMATOPOIETIC STEM CELL. DURING THE CHRONIC PHASE, PATIENTS PRESENT WITH A DRAMATIC EXPANSION OF MYELOID CELLS AND A MILD ANEMIA. RETROVIRAL GENE TRANSFER AND TRANSGENIC EXPRESSION IN RODENTS HAVE DEMONSTRATED THE ABILITY OF BCR-ABL TO INDUCE VARIOUS TYPES OF LEUKEMIA. HOWEVER, STUDY OF HUMAN CML OR RODENT MODELS HAS NOT DETERMINED THE DIRECT AND IMMEDIATE EFFECTS OF BCR-ABL ON HEMATOPOIETIC CELLS FROM THOSE REQUIRING SECONDARY GENETIC OR EPIGENETIC CHANGES SELECTED DURING THE PATHOGENIC PROCESS. WE UTILIZED TETRACYCLINE-REGULATED EXPRESSION OF BCR-ABL FROM A PROMOTER ENGINEERED FOR ROBUST EXPRESSION IN PRIMITIVE STEM CELLS THROUGH MULTILINEAGE BLOOD CELL DEVELOPMENT IN COMBINATION WITH THE IN VITRO DIFFERENTIATION OF EMBRYONAL STEM CELLS INTO HEMATOPOIETIC ELEMENTS. OUR RESULTS DEMONSTRATE THAT BCR-ABL EXPRESSION ALONE IS SUFFICIENT TO INCREASE THE NUMBER OF MULTIPOTENT AND MYELOID LINEAGE COMMITTED PROGENITORS IN A DOSE-DEPENDENT MANNER WHILE SUPPRESSING THE DEVELOPMENT OF COMMITTED ERYTHROID PROGENITORS. THESE EFFECTS ARE REVERSIBLE UPON EXTINGUISHING BCR-ABL EXPRESSION. THESE FINDINGS ARE CONSISTENT WITH BCR-ABL BEING THE SOLE GENETIC CHANGE NEEDED FOR THE ESTABLISHMENT OF THE CHRONIC PHASE OF CML AND PROVIDE A POWERFUL SYSTEM FOR THE ANALYSIS OF ANY GENETIC CHANGE THAT ALTERS CELL GROWTH AND LINEAGE CHOICES OF THE HEMATOPOIETIC STEM CELL. 2000 19 6249 36 THE METHYLATION STATUS OF THE MAJOR BREAKPOINT CLUSTER REGION IN HUMAN LEUKEMIA CELLS, INCLUDING PHILADELPHIA CHROMOSOME-POSITIVE CELLS, IS LINKED TO THE LINEAGE OF HEMATOPOIETIC CELLS. THE PHILADELPHIA (PH) TRANSLOCATION [T(9;22)(Q34;Q11)] IS THE MOST COMMON GENETIC ABNORMALITY IN HUMAN LEUKEMIA; A TRANSPOSITION OF THE ABL GENE TO THE MAJOR-BREAKPOINT CLUSTER REGION (M-BCR) IS ASSOCIATED WITH THE PATHOGENESIS IN PH+ CHRONIC MYELOGENOUS LEUKEMIA (PH+ CML) AND IN SOME CASES OF PH+ ACUTE LEUKEMIA (PH+ AL). OUR CURRENT UNDERSTANDING OF THE METHYLATION OF HUMAN GENOMES ALLOWS US TO CONSIDER THE ASSOCIATION BETWEEN THE EPIGENETIC PHENOMENON AND THE CONTROL OF DIFFERENTIATION AND PROLIFERATION IN MAMMALIAN CELLS. IN ORDER TO DETERMINE WHETHER THE METHYLATION STATUS OF THE M-BCR IS ASSOCIATED WITH BREAKPOINT-LOCALIZATION IN THIS REGION AND WITH THE LINEAGE OF HEMATOPOIETIC CELLS, WE HAVE EXAMINED 28 PATIENTS WITH PH+ LEUKEMIAS, INCLUDING NINE WITH PH+ AL, SIX PATIENTS WITH ACUTE MYELOBLASTIC LEUKEMIA WITHOUT PH (PH- AML), AND FIVE PATIENTS WITH PH- ACUTE LYMPHOBLASTIC LEUKEMIA (PH- ALL); USING THE RESTRICTION ENDONUCLEASE ISOCHIZOMERS, MSPI AND HPAII. IN CML PATIENTS IN THE CHRONIC PHASE, THE HYPOMETHYLATED STATUS WITHIN THE NORMAL M-BCR ALLELE IS HETEROGENEOUS. IN CONTRAST, PATIENTS WITH PH+ CML IN THE LYMPHOID BLAST CRISIS PHASE EXHIBITED A 2.5/2.7 KB BAND WITH A COMPLETE DISAPPEARANCE OF THE GERMLINE M-BCR FRAGMENT (TYPE L). THIS PATTERN IS CONSISTENTLY NOTED IN PH- ALL CELLS, AND THE PATTERN IS QUITE DIFFERENT FROM THAT FOUND IN MYELOID BLAST CRISIS OR PH- AML (TYPE M). IN PATIENTS WITH M-BCR-NONREARRANGED PH+ ALL, IT IS SUGGESTED THAT THE M-BCR METHYLATION PATTERNS ARE CELL-LINEAGE SPECIFIC BUT SOME PH+ ALL CELLS HAD A HYPOMETHYLATION PATTERN THAT WAS IDENTICAL TO THAT OBSERVED IN PH- AML, SUGGESTING A DISTINCTION OF GENETIC DIVERSITY OF LEUKEMIA CELLS WITH THE PH CHROMOSOME, ESPECIALLY PH+ AL. 1993 20 5691 37 SILENCING OF HDAC6 AS A THERAPEUTIC TARGET IN CHRONIC LYMPHOCYTIC LEUKEMIA. ALTHOUGH THE TREATMENT PARADIGM FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS RAPIDLY CHANGING, THE DISEASE REMAINS INCURABLE, EXCEPT WITH ALLOGENEIC BONE MARROW TRANSPLANTATION, AND RESISTANCE, RELAPSED DISEASE, AND PARTIAL RESPONSES PERSIST AS SIGNIFICANT CHALLENGES. RECENT STUDIES HAVE UNCOVERED ROLES FOR EPIGENETIC MODIFICATION IN THE REGULATION OF MECHANISMS CONTRIBUTING TO MALIGNANT PROGRESSION OF CLL B CELLS. HOWEVER, THE EXTENT TO WHICH EPIGENETIC MODIFIERS CAN BE TARGETED FOR THERAPEUTIC BENEFIT IN CLL PATIENTS REMAINS POORLY EXPLORED. WE REPORT FOR THE FIRST TIME THAT EXPRESSION OF EPIGENETIC MODIFIER HISTONE DEACETYLASE 6 (HDAC6) IS UPREGULATED IN CLL PATIENT SAMPLES, CELL LINES, AND EUTCL1 TRANSGENIC MOUSE MODELS COMPARED WITH HDAC6 IN NORMAL CONTROLS. GENETIC SILENCING OF HDAC6 CONFERRED SURVIVAL BENEFIT IN EUTCL1 MICE. ADMINISTRATION OF ISOFORM-SPECIFIC HDAC6 INHIBITOR ACY738 IN THE EUTCL1 AGING AND ADOPTIVE TRANSFER MODELS DETERRED PROLIFERATION OF CLL B CELLS, DELAYED DISEASE ONSET VIA DISRUPTION OF B-CELL RECEPTOR SIGNALING, AND SENSITIZED CLL B CELLS TO APOPTOSIS. FURTHERMORE, COADMINISTRATION OF ACY738 AND IBRUTINIB DISPLAYED SYNERGISTIC CELL KILL AGAINST CLL CELL LINES AND IMPROVED OVERALL SURVIVAL COMPARED WITH EITHER SINGLE AGENT IN VIVO. THESE RESULTS DEMONSTRATE FOR THE FIRST TIME THE THERAPEUTIC EFFICACY OF SELECTIVE HDAC6 INHIBITION IN PRECLINICAL CLL MODELS AND SUGGEST A RATIONALE FOR THE CLINICAL DEVELOPMENT OF HDAC6 INHIBITORS FOR CLL TREATMENT, EITHER ALONE OR IN COMBINATION WITH BRUTON TYROSINE KINASE INHIBITION. 2018