1 1860 137 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 2 825 48 CHARACTERIZATION OF FUNCTIONAL TRANSPOSABLE ELEMENT ENHANCERS IN ACUTE MYELOID LEUKEMIA. TRANSPOSABLE ELEMENTS (TES) HAVE BEEN SHOWN TO HAVE IMPORTANT GENE REGULATORY FUNCTIONS AND THEIR ALTERATION COULD LEAD TO DISEASE PHENOTYPES. ACUTE MYELOID LEUKEMIA (AML) DEVELOPS AS A CONSEQUENCE OF A SERIES OF GENETIC CHANGES IN HEMATOPOIETIC PRECURSOR CELLS, INCLUDING MUTATIONS IN EPIGENETIC FACTORS. HERE, WE SET OUT TO STUDY THE GENE REGULATORY ROLE OF TES IN AML. WE FIRST EXPLORED THE EPIGENETIC LANDSCAPE OF TES IN AML PATIENTS USING ATAC-SEQ DATA. WE SHOW THAT A LARGE NUMBER OF TES IN GENERAL, AND MORE SPECIFICALLY MAMMALIAN-WIDE INTERSPERSED REPEATS (MIRS), ARE MORE ENRICHED IN AML CELLS THAN IN NORMAL BLOOD CELLS. WE OBTAINED A SIMILAR FINDING WHEN ANALYZING HISTONE MODIFICATION DATA IN AML PATIENTS. GENE ONTOLOGY ENRICHMENT ANALYSIS SHOWED THAT GENES NEAR MIRS IN OPEN CHROMATIN REGIONS ARE INVOLVED IN LEUKEMOGENESIS. TO FUNCTIONALLY VALIDATE THEIR REGULATORY ROLE, WE SELECTED 19 MIR REGIONS IN AML CELLS, AND TESTED THEM FOR ENHANCER ACTIVITY IN AN AML CELL LINE (KASUMI-1) AND A CHRONIC MYELOID LEUKEMIA (CML) CELL LINE (K562); THE RESULTS REVEALED SEVERAL MIRS TO BE FUNCTIONAL ENHANCERS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT TES ARE POTENTIALLY INVOLVED IN MYELOID LEUKEMOGENESIS AND HIGHLIGHT THESE SEQUENCES AS POTENTIAL CANDIDATES HARBORING AML-ASSOCIATED VARIATION. 2020 3 3532 36 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 4 851 29 CHIP-SEQ ANALYSIS OF HUMAN CHRONIC MYELOID LEUKEMIA CELLS. MANY TRANSCRIPTION FACTORS, CHROMATIN-ASSOCIATED PROTEINS AND REGULATORY DNA ELEMENTS ARE GENETICALLY AND/OR EPIGENETICALLY ALTERED IN CANCER, INCLUDING CHRONIC MYELOID LEUKEMIA (CML). THIS LEADS TO DEREGULATION OF TRANSCRIPTION THAT IS OFTEN CAUSALLY LINKED TO THE TUMORIGENIC STATE. CHROMATIN-IMMUNOPRECIPITATION COUPLED WITH MASSIVELY PARALLEL DNA SEQUENCING (CHIP-SEQ) IS THE KEY TECHNOLOGY TO STUDY TRANSCRIPTION AS IT ALLOWS IN VIVO WHOLE-GENOME MAPPING OF EPIGENETIC MODIFICATIONS AND INTERACTIONS OF PROTEINS WITH DNA OR CHROMATIN. HOWEVER, NUMEROUS DNA/CHROMATIN-BINDING PROTEINS, INCLUDING EZH2, REMAIN DIFFICULT TO "CHIP," THUS YIELDING GENOME-WIDE BINDING MAPS OF ONLY SUBOPTIMAL QUALITY. HERE, WE DESCRIBE A CHIP-SEQ PROTOCOL OPTIMIZED FOR HIGH-QUALITY PROTEIN-GENOME BINDING MAPS THAT HAVE PROVEN ESPECIALLY USEFUL FOR STUDYING DIFFICULT TO 'CHIP' TRANSCRIPTION REGULATORY FACTORS IN CHRONIC MYELOID LEUKEMIA (CML) AND RELATED MALIGNANCIES. 2016 5 3415 42 HSP90 INHIBITION INCREASES SOCS3 TRANSCRIPT AND REGULATES MIGRATION AND CELL DEATH IN CHRONIC LYMPHOCYTIC LEUKEMIA. EPIGENETIC OR TRANSCRIPTIONAL SILENCING OF IMPORTANT TUMOR SUPPRESSORS HAS BEEN DESCRIBED TO CONTRIBUTE TO CELL SURVIVAL AND TUMORIGENESIS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). USING GENE EXPRESSION MICROARRAY ANALYSIS, WE FOUND THAT THOUSANDS OF GENES ARE REPRESSED MORE THAN 2-FOLD IN CLL COMPARED TO NORMAL B CELLS; HOWEVER THERAPEUTIC APPROACHES TO REVERSE THIS HAVE BEEN LIMITED IN CLL. FOLLOWING TREATMENT WITH THE HSP90 INHIBITOR 17-DMAG, A SIGNIFICANT NUMBER OF THESE REPRESSED GENES WERE SIGNIFICANTLY RE-EXPRESSED. ONE OF THE GENES SIGNIFICANTLY REPRESSED IN CLL AND UP-REGULATED BY 17-DMAG WAS SUPPRESSOR OF CYTOKINE SIGNALING 3, (SOCS3). SOCS3 HAS BEEN SHOWN TO BE SILENCED IN SOLID TUMORS AS WELL AS MYELOID LEUKEMIA; HOWEVER LITTLE IS KNOWN ABOUT THE REGULATION IN CLL. WE FOUND THAT 17-DMAG INDUCES EXPRESSION OF SOCS3 BY VIA THE ACTIVATION OF P38 SIGNALING, AND SUBSEQUENTLY INHIBITS AKT AND STAT3 PHOSPHORYLATION RESULTING IN DOWNSTREAM EFFECTS ON CELL MIGRATION AND SURVIVAL. WE THEREFORE SUGGEST THAT SOCS3 IS AN IMPORTANT SIGNALING PROTEIN IN CLL, AND HSP90 INHIBITORS REPRESENT A NOVEL APPROACH TO TARGET TRANSCRIPTIONAL REPRESSION IN B CELL LYMPHOPROLIFERATIVE DISORDERS WHICH EXHIBIT A SUBSTANTIAL DEGREE OF GENE REPRESSION. 2016 6 2025 36 EPIGENETIC CHANGES DURING DISEASE PROGRESSION IN A MURINE MODEL OF HUMAN CHRONIC LYMPHOCYTIC LEUKEMIA. EPIGENETIC ALTERATIONS, INCLUDING GAIN OR LOSS OF DNA METHYLATION, ARE A HALLMARK OF NEARLY EVERY MALIGNANCY. CHANGES IN DNA METHYLATION CAN IMPACT EXPRESSION OF CANCER-RELATED GENES INCLUDING APOPTOSIS REGULATORS AND TUMOR SUPPRESSORS. BECAUSE SUCH EPIGENETIC CHANGES ARE REVERSIBLE, THEY ARE BEING AGGRESSIVELY INVESTIGATED AS POTENTIAL THERAPEUTIC TARGETS. HERE WE USE THE EMU-TCL1 TRANSGENIC MOUSE MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TO DETERMINE THE TIMING AND PATTERNS OF ABERRANT DNA METHYLATION, AND TO INVESTIGATE THE MECHANISMS THAT LEAD TO ABERRANT DNA METHYLATION. WE SHOW THAT CLL CELLS FROM EMU-TCL1 MICE AT VARIOUS STAGES RECAPITULATE EPIGENETIC ALTERATIONS SEEN IN HUMAN CLL. ABERRANT METHYLATION OF PROMOTER SEQUENCES IS OBSERVED AS EARLY AS 3 MONTHS OF AGE IN THESE ANIMALS, WELL BEFORE DISEASE ONSET. ABNORMALLY METHYLATED PROMOTER REGIONS INCLUDE BINDING SITES FOR THE TRANSCRIPTION FACTOR FOXD3. WE SHOW THAT LOSS OF FOXD3 EXPRESSION DUE TO AN NF-KAPPAB P50/P50:HDAC1 REPRESSOR COMPLEX OCCURS IN TCL1-POSITIVE B CELLS BEFORE METHYLATION. THEREFORE, SPECIFIC TRANSCRIPTIONAL REPRESSION IS AN EARLY EVENT LEADING TO EPIGENETIC SILENCING OF TARGET GENES IN MURINE AND HUMAN CLL. THESE RESULTS PROVIDE STRONG RATIONALE FOR THE DEVELOPMENT OF STRATEGIES TO TARGET NF-KAPPAB COMPONENTS IN CLL AND POTENTIALLY OTHER B-CELL MALIGNANCIES. 2009 7 1542 39 DNA METHYLATION IN HAEMATOLOGICAL MALIGNANCIES: THE ROLE OF DECITABINE. NORMAL CELL DEVELOPMENT AND FUNCTION IS DEPENDENT UPON CONTROLLED GENE EXPRESSION. DNA METHYLATION IS AN EPIGENETIC MODIFICATION THAT CAN PLAY AN IMPORTANT ROLE IN THE CONTROL OF GENE EXPRESSION. DNA METHYLATION AT CYTOSINE RESIDUES IN GENE PROMOTER CPG SEQUENCES IS KNOWN TO INHIBIT GENE TRANSCRIPTION. INAPPROPRIATE INHIBITION OF THE TRANSCRIPTION OF TUMOUR SUPPRESSOR GENES, GENES THAT INHIBIT ANGIOGENESIS AND METASTASIS AND GENES INVOLVED IN DNA REPAIR BY UNCONTROLLED METHYLATION, CAN LEAD TO UNREGULATED GROWTH AND PROLIFERATION OF A CELL AND CARCINOGENESIS. PROMOTER HYPERMETHYLATION AFFECTING THE P16 GENE, RESULTING IN GENE SILENCING, HAS BEEN SHOWN TO OCCUR IN MANY HUMAN SOLID TUMOURS AND A 'HYPERMETHYLATION PROFILE' IN SOME LEUKAEMIAS HAS BEEN DEFINED. THE MOLECULAR MECHANISMS BY WHICH ABERRANT DNA METHYLATION TAKES PLACE DURING CARCINOGENESIS ARE STILL NOT CLEAR. HOWEVER, THE LARGE NUMBER OF TARGET GENES (INVOLVED IN TUMORIGENESIS) THAT ARE SILENCED BY ABERRANT METHYLATION SUGGESTS THAT INHIBITION OF THIS PROCESS MAY HAVE POTENTIAL AS CANCER THERAPY. DECITABINE (NSC-127716, DACOGEN; SUPERGEN) IS A POTENT AND SPECIFIC HYPOMETHYLATING AGENT AND AN INHIBITOR OF THE DNA METHYLTRANSFERASE ACTIVITY THAT MEDIATES DNA METHYLATION. DECITABINE HAS BEEN SHOWN TO HAVE A BROAD RANGE OF ANTINEOPLASTIC ACTIVITY IN PRECLINICAL STUDIES. THIS AGENT HAS EXHIBITED SIGNIFICANT ACTIVITY IN THE TREATMENT OF PATIENTS WITH MYELODYSPLASTIC SYNDROME, CHRONIC MYELOID LEUKAEMIA AND ACUTE MYELOID LEUKAEMIA, ALTHOUGH CLINICAL PHASE I AND II STUDIES WITH SOLID TUMOURS HAVE NOT BEEN VERY PROMISING. PHASE II AND III STUDIES ARE CURRENTLY ONGOING TO EVALUATE DECITABINE, BOTH ALONE AND IN COMBINATION, IN VARIOUS STAGES OF THESE HAEMATOLOGICAL MALIGNANCIES. 2003 8 4728 32 NOTCH SIGNALING PROMOTES DISEASE INITIATION AND PROGRESSION IN MURINE CHRONIC LYMPHOCYTIC LEUKEMIA. NOTCH1 GAIN-OF-FUNCTION MUTATIONS ARE RECURRENT IN B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL), WHERE THEY ARE ASSOCIATED WITH ACCELERATED DISEASE PROGRESSION AND REFRACTORINESS TO CHEMOTHERAPY. THE SPECIFIC ROLE OF NOTCH1 IN THE DEVELOPMENT AND PROGRESSION OF THIS MALIGNANCY IS UNCLEAR. HERE, WE ASSESS THE IMPACT OF LOSS OF NOTCH SIGNALING AND PATHWAY HYPERACTIVATION IN AN IN VIVO MOUSE MODEL OF CLL (IGH.TEMU) THAT FAITHFULLY REPLICATES MANY FEATURES OF THE HUMAN PATHOLOGY. ABLATION OF CANONICAL NOTCH SIGNALING USING CONDITIONAL GENE INACTIVATION OF RBP-J IN IMMATURE HEMATOPOIETIC OR B-CELL PROGENITORS DELAYED CLL INDUCTION AND REDUCED INCIDENCE OF MICE DEVELOPING DISEASE. IN CONTRAST, FORCED EXPRESSION OF A DOMINANT ACTIVE FORM OF NOTCH RESULTED IN MORE ANIMALS DEVELOPING CLL WITH EARLY DISEASE ONSET. COMPARATIVE ANALYSIS OF GENE EXPRESSION AND EPIGENETIC FEATURES OF NOTCH GAIN-OF-FUNCTION AND CONTROL CLL CELLS REVEALED DIRECT AND INDIRECT REGULATION OF CELL CYCLE-ASSOCIATED GENES, WHICH LED TO INCREASED PROLIFERATION OF NOTCH GAIN-OF-FUNCTION CLL CELLS IN VIVO. THESE RESULTS DEMONSTRATE THAT NOTCH SIGNALING FACILITATES DISEASE INITIATION AND PROMOTES CLL CELL PROLIFERATION AND DISEASE PROGRESSION. 2021 9 390 42 AN INTEGRATIVE MODEL OF PATHWAY CONVERGENCE IN GENETICALLY HETEROGENEOUS BLAST CRISIS CHRONIC MYELOID LEUKEMIA. TARGETED THERAPIES AGAINST THE BCR-ABL1 KINASE HAVE REVOLUTIONIZED TREATMENT OF CHRONIC PHASE (CP) CHRONIC MYELOID LEUKEMIA (CML). IN CONTRAST, MANAGEMENT OF BLAST CRISIS (BC) CML REMAINS CHALLENGING BECAUSE BC CELLS ACQUIRE COMPLEX MOLECULAR ALTERATIONS THAT CONFER STEMNESS FEATURES TO PROGENITOR POPULATIONS AND RESISTANCE TO BCR-ABL1 TYROSINE KINASE INHIBITORS. COMPREHENSIVE MODELS OF BC TRANSFORMATION HAVE PROVED ELUSIVE BECAUSE OF THE RARITY AND GENETIC HETEROGENEITY OF BC, BUT ARE IMPORTANT FOR DEVELOPING BIOMARKERS PREDICTING BC PROGRESSION AND EFFECTIVE THERAPIES. TO BETTER UNDERSTAND BC, WE PERFORMED AN INTEGRATED MULTIOMICS ANALYSIS OF 74 CP AND BC SAMPLES USING WHOLE-GENOME AND EXOME SEQUENCING, TRANSCRIPTOME AND METHYLOME PROFILING, AND CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY HIGH-THROUGHPUT SEQUENCING. EMPLOYING PATHWAY-BASED ANALYSIS, WE FOUND THE BC GENOME WAS SIGNIFICANTLY ENRICHED FOR MUTATIONS AFFECTING COMPONENTS OF THE POLYCOMB REPRESSIVE COMPLEX (PRC) PATHWAY. WHILE TRANSCRIPTOMICALLY, BC PROGENITORS WERE ENRICHED AND DEPLETED FOR PRC1- AND PRC2-RELATED GENE SETS RESPECTIVELY. BY INTEGRATING OUR DATA SETS, WE DETERMINED THAT BC PROGENITORS UNDERGO PRC-DRIVEN EPIGENETIC REPROGRAMMING TOWARD A CONVERGENT TRANSCRIPTOMIC STATE. SPECIFICALLY, PRC2 DIRECTS BC DNA HYPERMETHYLATION, WHICH IN TURN SILENCES KEY GENES INVOLVED IN MYELOID DIFFERENTIATION AND TUMOR SUPPRESSOR FUNCTION VIA SO-CALLED EPIGENETIC SWITCHING, WHEREAS PRC1 REPRESSES AN OVERLAPPING AND DISTINCT SET OF GENES, INCLUDING NOVEL BC TUMOR SUPPRESSORS. ON THE BASIS OF THESE OBSERVATIONS, WE DEVELOPED AN INTEGRATED MODEL OF BC THAT FACILITATED THE IDENTIFICATION OF COMBINATORIAL THERAPIES CAPABLE OF REVERSING BC REPROGRAMMING (DECITABINE+PRC1 INHIBITORS), NOVEL PRC-SILENCED TUMOR SUPPRESSOR GENES (NR4A2), AND GENE EXPRESSION SIGNATURES PREDICTIVE OF DISEASE PROGRESSION AND DRUG RESISTANCE IN CP. 2020 10 59 42 A GENOME-WIDE SCREEN IDENTIFIES FREQUENTLY METHYLATED GENES IN HAEMATOLOGICAL AND EPITHELIAL CANCERS. BACKGROUND: GENETIC AS WELL AS EPIGENETIC ALTERATIONS ARE A HALLMARK OF BOTH EPITHELIAL AND HAEMATOLOGICAL MALIGNANCIES. HIGH THROUGHPUT SCREENS ARE REQUIRED TO IDENTIFY EPIGENETIC MARKERS THAT CAN BE USEFUL FOR DIAGNOSTIC AND PROGNOSTIC PURPOSES ACROSS MALIGNANCIES. RESULTS: HERE WE REPORT FOR THE FIRST TIME THE USE OF THE MIRA ASSAY (METHYLATED CPG ISLAND RECOVERY ASSAY) IN COMBINATION WITH GENOME-WIDE CPG ISLAND ARRAYS TO IDENTIFY EPIGENETIC MOLECULAR MARKERS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) ON A GENOME-WIDE SCALE. WE IDENTIFIED 30 GENES DEMONSTRATING METHYLATION FREQUENCIES OF > OR =25% IN CHILDHOOD ALL, NINE GENES SHOWED SIGNIFICANTLY DIFFERENT METHYLATION FREQUENCIES IN B VS T-ALL. FOR MAJORITY OF THE GENES EXPRESSION COULD BE RESTORED IN METHYLATED LEUKEMIA LINES AFTER TREATMENT WITH 5-AZADC. FORTY-FOUR PERCENT OF THE GENES REPRESENT TARGETS OF THE POLYCOMB COMPLEX. IN CHRONIC MYELOID LEUKEMIA (CML) TWO OF THE GENES, (TFAP2A AND EBF2), DEMONSTRATED INCREASED METHYLATION IN BLAST CRISIS COMPARED TO CHRONIC PHASE (P < 0.05). FURTHERMORE HYPERMETHYLATION OF AN AUTOPHAGY RELATED GENE ATG16L2 WAS ASSOCIATED WITH POORER PROGNOSIS IN TERMS OF MOLECULAR RESPONSE TO IMATINIB TREATMENT. LASTLY WE DEMONSTRATED THAT TEN OF THESE GENES WERE ALSO FREQUENTLY METHYLATED IN COMMON EPITHELIAL CANCERS. CONCLUSION: IN SUMMARY WE HAVE IDENTIFIED A LARGE NUMBER OF GENES SHOWING FREQUENT METHYLATION IN CHILDHOOD ALL, METHYLATION STATUS OF TWO OF THESE GENES IS ASSOCIATED WITH ADVANCED DISEASE IN CML AND METHYLATION STATUS OF ANOTHER GENE IS ASSOCIATED WITH PROGNOSIS. IN ADDITION A SUBSET OF THESE GENES MAY ACT AS EPIGENETIC MARKERS ACROSS HEMATOLOGICAL MALIGNANCIES AS WELL AS COMMON EPITHELIAL CANCERS. 2010 11 1568 23 DNA METHYLATION OF TUMOR-SUPPRESSOR MIRNA GENES IN CHRONIC LYMPHOCYTIC LEUKEMIA. DNA METHYLATION IS ONE OF THE MOST IMPORTANT EPIGENETIC MODIFICATIONS OF THE GENOME INVOLVED IN THE REGULATION OF NUMEROUS CELLULAR PROCESSES THROUGH GENE SILENCING WITHOUT ALTERING DNA SEQUENCES. MIRNAS, A CLASS OF SINGLE-STRANDED NONCODING RNAS OF 19-25 NUCLEOTIDES IN LENGTH, FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS OF GENE EXPRESSION LEADING TO MRNA CLEAVAGE OR TRANSLATIONAL REPRESSION OF THEIR CORRESPONDING TARGET PROTEIN-CODING GENES. RECENTLY, DYSREGULATION OF TUMOR SUPPRESSOR MIRNAS MEDIATED BY PROMOTER DNA HYPERMETHYLATION IS IMPLICATED IN HUMAN CANCERS, INCLUDING B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). MOREOVER, IT APPEARS THAT METHYLATED MIRNA GENES COULD BE POTENTIAL BIOMARKERS FOR CLL DIAGNOSIS OR THERAPY. THIS REVIEW WILL HIGHLIGHT THE ROLE OF ABERRANT METHYLATION OF MIRNA GENES IN THE PATHOGENESIS OF CLL. 2015 12 1465 30 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 13 5259 37 PROGRESSIVE DE NOVO DNA METHYLATION AT THE BCR-ABL LOCUS IN THE COURSE OF CHRONIC MYELOGENOUS LEUKEMIA. DE NOVO METHYLATION OF CPG ISLANDS IS A RARE EVENT IN MAMMALIAN CELLS. IT HAS BEEN OBSERVED IN THE COURSE OF DEVELOPMENTAL PROCESSES, SUCH AS X CHROMOSOME INACTIVATION AND GENOMIC IMPRINTING. THE METHYLATION OF DNA, AN IMPORTANT FACTOR IN THE EPIGENETIC CONTROL OF GENE EXPRESSION, MAY ALSO BE INVOLVED IN TUMORIGENESIS. AFTER THE T(9;22) CHROMOSOMAL TRANSLOCATION AND GENERATION OF THE PHILADELPHIA CHROMOSOME, THE INITIATING EVENT IN CHRONIC MYELOGENOUS LEUKEMIA (CML), MOST OF THE ABL CODING SEQUENCE IS FUSED TO THE 5' REGION OF THE BCR GENE. EXPRESSION OF THE HYBRID BCR-ABL GENE IS, THEREFORE, REGULATED BY THE BCR PROMOTER. IN MOST CASES OF CML, ONE OF THE TWO ABL PROMOTERS (PA) IS NESTED WITHIN THE BCR-ABL TRANSCRIPTIONAL UNIT AND SHOULD BE ABLE TO TRANSCRIBE THE TYPE IA 6-KB NORMAL ABL MRNA FROM THE PHILADELPHIA CHROMOSOME. HOWEVER, WE HAVE FOUND THAT THE 6-KB TRANSCRIPT IS PRESENT ONLY IN CML CELL LINES CONTAINING A NORMAL ABL ALLELE AND THAT THE APPARENT INACTIVATION OF THE NESTED PA PROMOTER IS ASSOCIATED WITH ALLELE-SPECIFIC METHYLATION. FURTHERMORE, WE HAVE NOTICED THAT THE PA PROMOTER IS CONTAINED WITHIN A CPG ISLAND AND UNDERGOES PROGRESSIVE DE NOVO METHYLATION IN THE COURSE OF THE DISEASE. THIS IS ATTESTED TO BY THE FACT THAT DNA SAMPLES FROM CML PATIENTS THAT ARE METHYLATION-FREE AT THE TIME OF DIAGNOSIS INVARIABLY BECOME METHYLATED IN ADVANCED CML. SINCE TUMOR PROGRESSION IN CML CANNOT ALWAYS BE INFERRED FROM THE CLINICAL PRESENTATION, ASSESSMENT OF DE NOVO CPG METHYLATION MAY PROVE TO BE OF CRITICAL VALUE IN MANAGEMENT OF THE DISEASE. IT COULD HERALD BLASTIC TRANSFORMATION AT A STAGE WHEN BONE MARROW TRANSPLANTATION, THE ONLY POTENTIALLY CURATIVE THERAPEUTIC PROCEDURE IN CML, IS STILL EFFECTIVE. 1994 14 1976 34 EPIGENETIC ALTERATIONS IN A MURINE MODEL FOR CHRONIC LYMPHOCYTIC LEUKEMIA. EARLY STAGES IN THE DEVELOPMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAVE NOT BEEN EXPLORED MAINLY DUE TO THE INABILITY TO STUDY NORMAL B-CELLS EN ROUTE TO TRANSFORMATION. IN ORDER TO DETERMINE SUCH EARLY EVENTS OF LEUKEMOGENESIS, WE HAVE USED A WELL ESTABLISHED MOUSE MODEL FOR CLL. OVER-EXPRESSION OF HUMAN TCL1, A KNOWN CLL ONCOGENE IN MURINE B-CELLS LEADS TO THE DEVELOPMENT OF MATURE CD19+/CD5+/IGM+ CLONAL LEUKEMIA WITH A DISEASE PHENOTYPE SIMILAR TO THAT SEEN IN HUMAN CLL. HEREIN, WE REVIEW OUR RECENT STUDY USING THIS TCL1-DRIVEN MOUSE MODEL FOR CLL AND CORRESPONDING HUMAN CLL SAMPLES IN A CROSS-SPECIES EPIGENOMICS APPROACH TO ADDRESS THE TIMING AND RELEVANCE OF EPIGENETIC EVENTS OCCURRING DURING LEUKEMOGENESIS. WE DEMONSTRATED THAT THE MOUSE MODEL RECAPITULATES THE EPIGENETIC EVENTS THAT HAVE BEEN REPORTED FOR HUMAN CLL, AFFIRMING THE POWER AND VALIDITY OF THIS MOUSE MODEL TO STUDY EARLY EPIGENETIC EVENTS IN CANCER PROGRESSION. EPIGENETIC ALTERATIONS ARE DETECTED AS EARLY AS THREE MONTHS AFTER BIRTH, FAR BEFORE DISEASE MANIFESTS AT ABOUT 11 MONTHS OF AGE. THESE MICE UNDERGO NFKAPPAB REPRESSOR COMPLEX MEDIATED INACTIVATION OF THE TRANSCRIPTION FACTOR FOXD3, WHOSE TARGETS BECOME ABERRANTLY METHYLATED AND SILENCED IN MOUSE AND HUMAN CLL. OVERALL, OUR DATA SUGGEST THE ACCUMULATED EPIGENETIC ALTERATIONS DURING CLL PATHOGENESIS AS A CONSEQUENCE OF GENE SILENCING THROUGH TCL1 AND NFKAPPAB REPRESSOR COMPLEX, SUGGESTING THE RELEVANCE FOR NFKAPPAB AS A THERAPEUTIC TARGET IN CLL. 2009 15 206 37 ACTIVATION OF NOTCH AND MYC SIGNALING VIA B-CELL-RESTRICTED DEPLETION OF DNMT3A GENERATES A CONSISTENT MURINE MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY DISORDERED DNA METHYLATION, SUGGESTING THESE EPIGENETIC CHANGES MIGHT PLAY A CRITICAL ROLE IN DISEASE ONSET AND PROGRESSION. THE METHYLTRANSFERASE DNMT3A IS A KEY REGULATOR OF DNA METHYLATION. ALTHOUGH DNMT3A SOMATIC MUTATIONS IN CLL ARE RARE, WE FOUND THAT LOW DNMT3A EXPRESSION IS ASSOCIATED WITH MORE AGGRESSIVE DISEASE. A CONDITIONAL KNOCKOUT MOUSE MODEL SHOWED THAT HOMOZYGOUS DEPLETION OF DNMT3A FROM B CELLS RESULTS IN THE DEVELOPMENT OF CLL WITH 100% PENETRANCE AT A MEDIAN AGE OF ONSET OF 5.3 MONTHS, AND HETEROZYGOUS DNMT3A DEPLETION YIELDS A DISEASE PENETRANCE OF 89% WITH A MEDIAN ONSET AT 18.5 MONTHS, CONFIRMING ITS ROLE AS A HAPLOINSUFFICIENT TUMOR SUPPRESSOR. B1A CELLS WERE CONFIRMED AS THE CELL OF ORIGIN OF DISEASE IN THIS MODEL, AND DNMT3A DEPLETION RESULTED IN FOCAL HYPOMETHYLATION AND ACTIVATION OF NOTCH AND MYC SIGNALING. AMPLIFICATION OF CHROMOSOME 15 CONTAINING THE MYC GENE WAS DETECTED IN ALL CLL MICE TESTED, AND INFILTRATION OF HIGH-MYC-EXPRESSING CLL CELLS IN THE SPLEEN WAS OBSERVED. NOTABLY, HYPERACTIVATION OF NOTCH AND MYC SIGNALING WAS EXCLUSIVELY OBSERVED IN THE DNMT3A CLL MICE, BUT NOT IN THREE OTHER CLL MOUSE MODELS TESTED (SF3B1-ATM, IKZF3, AND MDR), AND DNMT3A-DEPLETED CLL WERE SENSITIVE TO PHARMACOLOGIC INHIBITION OF NOTCH SIGNALING IN VITRO AND IN VIVO. CONSISTENT WITH THESE FINDINGS, HUMAN CLL SAMPLES WITH LOWER DNMT3A EXPRESSION WERE MORE SENSITIVE TO NOTCH INHIBITION THAN THOSE WITH HIGHER DNMT3A EXPRESSION. ALTOGETHER, THESE RESULTS SUGGEST THAT DNMT3A DEPLETION INDUCES CLL THAT IS HIGHLY DEPENDENT ON ACTIVATION OF NOTCH AND MYC SIGNALING. SIGNIFICANCE: LOSS OF DNMT3A EXPRESSION IS A DRIVING EVENT IN CLL AND IS ASSOCIATED WITH AGGRESSIVE DISEASE, ACTIVATION OF NOTCH AND MYC SIGNALING, AND ENHANCED SENSITIVITY TO NOTCH INHIBITION. 2021 16 358 40 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML. 2013 17 6773 26 [ADVANCES OF RESEARCH ON DEMETHYLATION THERAPY FOR HEMATOLOGIC MALIGNANCIES]. DNA METHYLATION IS AN IMPORTANT AND REVERSIBLE EPIGENETIC MODIFICATION WHICH REGULATES GENOMIC STABILITY. METHYLATION IS ESSENTIAL FOR MAMMALIAN DEVELOPMENT. GENERALLY, GENE EXPRESSION LEVEL AND DNA METHYLATION ARE NEGATIVE CORRELATION. TRANSCRIPTIONAL SILENCING VIA METHYLATION OF CPG ISLANDS IN THE PROMOTER IS IMPORTANT FOR CELL GROWTH AND DIFFERENTIATION AND PLAYS A KEY ROLE IN TUMORIGENESIS. DEMETHYLATION DRUG CAN MODIFY CHROMATIN AND RESTORE THE ABILITY OF ANTI-ONCOGENE. DEMETHYLATION THERAPY AS A NEW THERAPY MAY TREAT EFFICIENTLY HEMATOLOGICAL MALIGNANCIES WITH RESISTANCE AND RELAPSE. IN THIS REVIEW, DNA METHYLATION MECHANISM, RELATIONSHIP BETWEEN ABERRANT METHYLATION AND HEMATOLOGIC MALIGNANCIES, MECHANISM OF DEMETHYLATION THERAPY, THE ADVANCE OF RESEARCH ON THE DEMETHYLATION THERAPY OF HEMATOLOGICAL MALIGNANCIES, SUCH AS ACUTE AND CHRONIC LEUKEMIA, LYMPHOMA, MYELODYSPLASTIC SYNDROME WERE SUMMARIZED. 2009 18 2747 37 EXPRESSION ANALYSIS OF THE EPIGENETIC METHYLTRANSFERASES AND METHYL-CPG BINDING PROTEIN FAMILIES IN THE NORMAL B-CELL AND B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN CARCINOGENESIS HAS BEEN A SOURCE OF CONTROVERSY FOR SOME TIME. THERE IS LITTLE DOUBT THAT CHANGES IN GENOMIC HYPERMETHYLATION CONTRIBUTE TO THE SILENCING OF TUMOR SUPPRESSOR GENES. FURTHERMORE, RECENT STUDIES HAVE ALSO IDENTIFIED THE SIGNIFICANCE OF GENOMIC HYPOMETHYLATION ASSOCIATED WITH CHROMOSOMAL INSTABILITY AND TUMORIGENESIS. ONE OF THE MOST PERPLEXING QUESTIONS REGARDING EPIGENETIC MODIFICATIONS AND LEUKEMOGENESIS IS THE RELATIONSHIP WITH DNA METHYLTRANSFERASES (DNMT'S). THE PRIMARY FUNCTION OF THE DNMT ENZYMES IS TO METHYLATE GENOMIC DNA, WHEREAS THE METHYL-CPG BINDING DOMAIN PROTEINS (MBD) INTERPRET THIS METHYLATION SIGNAL AND REGULATE GENE EXPRESSION AND CHROMATIN BEHAVIOR. IN THIS STUDY WE ANALYSE THESE GENE FAMILIES BY QUANTITATIVE REAL-TIME PCR TO INVESTIGATE WHETHER EXPRESSION LEVELS AND THE B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) PHENOTYPE ARE ASSOCIATED. FURTHERMORE, GIVEN THE EPIGENETIC CROSSTALK BETWEEN GENOME STABILITY AND THE HISTONE CHROMATIN CODE WE HAVE ANALYSED EUKARYOTIC HISTONE METHYLTRANSFERASE (EU-HMTASEI). SURPRISINGLY, WE DID NOT OBSERVE SIGNIFICANT CHANGES IN DNMT1 EXPRESSION IN B-CLL CASES WHEN COMPARED TO NORMAL LYMPHOCYTES, REGARDLESS OF WHETHER WE NORMALISE AGAINST GAPDH OR PCNA AS REFERENCE STANDARDS. INDEED, EXPRESSION OF THE MAINTENANCE AND DE NOVO METHYLASES WERE INDEPENDENTLY REGULATED. OF PARTICULAR NOTE WAS THE SIGNIFICANT DOWN REGULATION OF DNMT3B. FURTHERMORE, WE OBSERVED A POSITIVE CORRELATION BETWEEN HMTASEI EXPRESSION LEVELS AND STAGE OF LEUKEMIA SUGGESTING THAT CHANGES IN THE METHYLATION PATTERNS IN B-CLL MAY REPRESENT DEREGULATION OF THE EPIGENETIC REPERTOIRE THAT ALSO INCLUDE THE METHYLATION DEPENDENT BINDING PROTEINS, MBD2 AND MECP2. WE ENVISAGE CHANGES IN THE EPIGENETIC PROGRAM ARE MULTIFACTORIAL IN NATURE AND POSTULATE THAT THE PREVALENT GENOMIC METHYLASES JUST ONE COMPONENT OF A LARGER EPIGENETIC REPERTOIRE. 2004 19 2781 33 EZH2 IN MYELOID MALIGNANCIES. OUR UNDERSTANDING OF THE SIGNIFICANCE OF EPIGENETIC DYSREGULATION IN THE PATHOGENESIS OF MYELOID MALIGNANCIES HAS GREATLY ADVANCED IN THE PAST DECADE. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS THE CATALYTIC CORE COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), WHICH IS RESPONSIBLE FOR GENE SILENCING THROUGH TRIMETHYLATION OF H3K27. EZH2 DYSREGULATION IS HIGHLY TUMORIGENIC AND HAS BEEN OBSERVED IN VARIOUS CANCERS, WITH EZH2 ACTING AS AN ONCOGENE OR A TUMOR-SUPPRESSOR DEPENDING ON CELLULAR CONTEXT. WHILE LOSS-OF-FUNCTION MUTATIONS OF EZH2 FREQUENTLY AFFECT PATIENTS WITH MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS, MYELODYSPLASTIC SYNDROME AND MYELOFIBROSIS, CASES OF CHRONIC MYELOID LEUKEMIA (CML) SEEM TO BE LARGELY CHARACTERIZED BY EZH2 OVEREXPRESSION. A VARIETY OF OTHER FACTORS FREQUENTLY ABERRANT IN MYELOID LEUKEMIA CAN AFFECT PRC2 FUNCTION AND DISEASE PATHOGENESIS, INCLUDING ADDITIONAL SEX COMBS LIKE 1 (ASXL1) AND SPLICING GENE MUTATIONS. AS THE GENETIC BACKGROUND OF MYELOID MALIGNANCIES IS LARGELY HETEROGENEOUS, IT IS NOT SURPRISING THAT EZH2 MUTATIONS ACT IN CONJUNCTION WITH OTHER ABERRATIONS. SINCE EZH2 MUTATIONS ARE CONSIDERED TO BE EARLY EVENTS IN DISEASE PATHOGENESIS, THEY ARE OF THERAPEUTIC INTEREST TO RESEARCHERS, THOUGH TARGETING OF EZH2 LOSS-OF-FUNCTION DOES PRESENT UNIQUE CHALLENGES. PRELIMINARY RESEARCH INDICATES THAT COMBINED TYROSINE KINASE INHIBITOR (TKI) AND EZH2 INHIBITOR THERAPY MAY PROVIDE A STRATEGY TO ELIMINATE THE RESIDUAL DISEASE BURDEN IN CML TO ALLOW PATIENTS TO REMAIN IN TREATMENT-FREE REMISSION. 2020 20 2752 41 EXPRESSION OF ANGIOGENIC FACTORS IN CHRONIC MYELOID LEUKAEMIA: ROLE OF THE BCR/ABL ONCOGENE, BIOCHEMICAL MECHANISMS, AND POTENTIAL CLINICAL IMPLICATIONS. CHRONIC MYELOID LEUKAEMIA (CML) IS A STEM CELL DISEASE CHARACTERIZED BY AN INCREASED PRODUCTION AND ACCUMULATION OF CLONAL BCR/ABL-POSITIVE CELLS IN HAEMATOPOIETIC TISSUES. THE CHRONIC PHASE OF CML IS INEVITABLY FOLLOWED BY AN ACCELERATED PHASE OF THE DISEASE, WITH CONSECUTIVE BLAST CRISIS. HOWEVER, DEPENDING ON GENETIC STABILITY, EPIGENETIC EVENTS, AND SEVERAL OTHER FACTORS, THE CLINICAL COURSE AND SURVIVAL APPEAR TO VARY AMONG PATIENTS. RECENT DATA SUGGEST THAT ANGIOGENIC CYTOKINES SUCH AS VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF), ARE UP-REGULATED IN CML, AND PLAY A ROLE IN THE PATHOGENESIS OF THE DISEASE. THESE FACTORS APPEAR TO BE PRODUCED AND RELEASED IN LEUKAEMIC CELLS IN PATIENTS WITH CML. IN LINE WITH THIS NOTION, INCREASED SERUM-LEVELS OF ANGIOGENIC GROWTH FACTORS ARE MEASURABLE IN CML PATIENTS. IN THIS STUDY WE PROVIDE AN OVERVIEW OF ANGIOGENIC GROWTH FACTORS EXPRESSED IN CML CELLS, DISCUSS THE POSSIBLE PATHOGENETIC ROLE OF THESE CYTOKINES, THE BIOCHEMICAL BASIS OF THEIR PRODUCTION IN LEUKAEMIC CELLS, AND THEIR POTENTIAL CLINICAL IMPLICATIONS. 2004