1 5514 131 RICHTER'S SYNDROME: BIOLOGY AND THERAPY. RICHTER'S SYNDROME, THAT IS, TRANSFORMATION OF CHRONIC LYMPHOCYTIC LEUKEMIA TO A LARGE CELL OR IMMUNOBLASTIC LYMPHOMA, OCCURS IN UP TO 10% OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. THE ONSET OF RICHTER'S SYNDROME IS CHARACTERIZED BY WORSENING SYSTEMIC SYMPTOMS, RAPID TUMOR GROWTH, AND/OR EXTRANODAL INVOLVEMENT. MEDIAN SURVIVAL WITH CONVENTIONAL CHEMOTHERAPY IS LESS THAN 6 MONTHS. THERAPY WITH MORE RECENT THERAPEUTIC REGIMENS, SUCH AS HYPERCVXD (FRACTIONATED CYCLOPHOSPHAMIDE, VINCRISTINE, LIPOSOMAL DAUNORUBICIN, AND DEXAMETHASONE), AUGMENTED HYPERCVXD, AND YTTRIUM-90 IBRITUMOMAB TIUXETAN, HAS NOT PRODUCED MAJOR IMPROVEMENTS IN RESPONSE RATES OR OVERALL SURVIVAL. IMPROVEMENT IN THE OUTCOME OF PATIENTS WITH RICHTER'S SYNDROME MAY BE AIDED BY A MORE COMPREHENSIVE UNDERSTANDING OF THE PATHOGENESIS OF RICHTER'S SYNDROME; THERAPY COULD THEN BE TARGETED AGAINST SPECIFIC ABNORMALITIES. CURRENT DATA INDICATE THAT THE TRANSFORMATION OF CHRONIC LYMPHOCYTIC LEUKEMIA TO A LARGE-CELL OR IMMUNOBLASTIC LYMPHOMA IS ASSOCIATED WITH ABNORMALITIES IN CELL CYCLE REGULATION (E.G., LOSS OF THE CELL CYCLE INHIBITORS P16(INK4A) AND P27(KIP1) ) AND DNA REPAIR (E.G., MUTATIONS AND/OR DELETIONS OF THE P53, ATM, AND P14(ARF) GENES AND EPIGENETIC SILENCING OF THE MLH1 GENE). HOWEVER, THE CRITICAL EVENT LEADING TO TRANSFORMATION IS UNCLEAR. GIVEN THE POOR PROGNOSIS OF PATIENTS WITH RICHTER'S SYNDROME, EVERY EFFORT SHOULD BE MADE TO ENROLL THESE PATIENTS INTO CLINICAL TRIALS EVALUATING NOVEL AGENTS WITH THE APPROPRIATE CORRELATIVE STUDIES. 2005 2 1260 31 CURRENT VIEWS ON THE INTERPLAY BETWEEN TYROSINE KINASES AND PHOSPHATASES IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY BCR-ABL1 ONCOGENE EXPRESSION. THIS DYSREGULATED PROTEIN-TYROSINE KINASE (PTK) IS KNOWN AS THE PRINCIPAL DRIVER OF THE DISEASE AND IS TARGETED BY TYROSINE KINASE INHIBITORS (TKIS). EXTENSIVE DOCUMENTATION HAS ELUCIDATED HOW THE TRANSFORMATION OF MALIGNANT CELLS IS CHARACTERIZED BY MULTIPLE GENETIC/EPIGENETIC CHANGES LEADING TO THE LOSS OF TUMOR-SUPPRESSOR GENES FUNCTION OR PROTO-ONCOGENES EXPRESSION. THE IMPAIRMENT OF ADEQUATE LEVELS OF SUBSTRATES PHOSPHORYLATION, THUS AFFECTING THE BALANCE PTKS AND PROTEIN PHOSPHATASES (PPS), REPRESENTS A WELL-ESTABLISHED CELLULAR MECHANISM TO ESCAPE FROM SELF-LIMITING SIGNALS. IN THIS REVIEW, WE FOCUS OUR ATTENTION ON THE CHARACTERIZATION OF AND INTERACTIONS BETWEEN PTKS AND PPS, EMPHASIZING THEIR BIOLOGICAL ROLES IN DISEASE EXPANSION, THE REGULATION OF LSCS AND TKI RESISTANCE. WE DECIDED TO SEPARATE THOSE PPS THAT HAVE BEEN VALIDATED IN PRIMARY CELL MODELS OR LEUKEMIA MOUSE MODELS FROM THOSE WHOSE STUDIES HAVE BEEN PERFORMED ONLY IN CELL LINES (AND, THUS, REQUIRE VALIDATION), AS THERE MAY BE DIFFERENCES IN THE MANNER THAT THE ASSOCIATED PATHWAYS ARE MODIFIED UNDER THESE TWO CONDITIONS. THIS REVIEW SUMMARIZES THE ROLES OF DIVERSE PPS, WITH HOPE THAT BETTER KNOWLEDGE OF THE INTERPLAY AMONG PHOSPHATASES AND KINASES WILL EVENTUALLY RESULT IN A BETTER UNDERSTANDING OF THIS DISEASE AND CONTRIBUTE TO ITS ERADICATION. 2021 3 2025 31 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 4 5691 35 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 5 2935 33 GENETIC ALTERATION ASSOCIATED WITH CHRONIC LYMPHOCYTIC LEUKEMIA. THE GENETICS OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) DIFFER CONSIDERABLY FROM MOST OTHER FORMS OF HEMATOLOGIC MALIGNANCY WHICH ARE USUALLY CHARACTERIZED BY CHROMOSOME TRANSLOCATIONS. B-CLL TYPICALLY CONTAINS CHROMOSOMAL DELETIONS AND CHROMOSOMES 13Q14 AND 11Q22-->Q23 ARE THE MOST COMMON. THESE TWO REGIONS APPEAR TO SHARE A COMMON ANCESTRAL ORIGIN (AUER ET AL., 2007B). OVERALL, CHROMOSOMAL ABNORMALITIES CAN BE FOUND IN THE MAJORITY OF PATIENTS WITH B-CLL WHEN USING SENSITIVE TECHNIQUES (DOHNERET AL., 2000) AND POSSIBLY REFLECTS AN UNDERLYING PREDISPOSITION, WITH A SMALL BUT SIGNIFICANT NUMBER OF FAMILIAL CASES. ALTHOUGH SINGLE AND CONSISTENT ABNORMALITIES ARE MOST COMMON, MULTIPLE REARRANGEMENTS CAN OCCUR, OFTEN WITH DISEASE PROGRESSION (FEGANETAL., 1995; DOHNER ET AL., 2000). REGIONS OF RECURRENT DELETION SUGGEST THE PRESENCE OF TUMOR SUPPRESSOR GENES IF FOLLOWING KNUDSON'S THEORETICAL 2-HIT MODEL. HOWEVER, DESPITE EXTENSIVE SEQUENCING ANALYSIS OVER THE LAST DECADE AND LACK OF PATHOGENIC MUTATIONS IDENTIFIED, THERE HAS BEEN A MOVE AWAY FROM THIS SUGGESTED HYPOTHESIS AND ALTERNATIVE MECHANISMS OF GENE INACTIVATION INVOLVING EPIGENETIC SILENCING OR HAPLOINSUFFICIENCY MAY BE CONSIDERED AS MORE LIKELY IN THIS DISEASE. THIS REVIEW FOCUSES ON THE COMMON GENETIC ABNORMALITIES IN B-CLL AND RELATES THEM TO SOME OF THE MORE RECENT HYPOTHESES ON INACTIVATION OF GENES WITHIN THESE REGIONS OF DELETION. 2007 6 358 35 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 7 3565 34 IMPACT OF GENETIC POLYMORPHISMS AND BIOMARKERS ON THE EFFECTIVENESS AND TOXICITY OF TREATMENT OF CHRONIC MYELOID LEUKEMIA AND ACUTE MYELOID LEUKEMIA. MOST MALIGNANT HEMATOLOGICAL DISEASES ARE GENERALLY A CONSEQUENCE OF ACQUIRED MUTATIONS OR REARRANGEMENTS IN CELL REPLICATION PROCESSES. ACUTE MYELOID LEUKEMIA (AML) IS A CLINICALLY AND MOLECULARLY HETEROGENEOUS DISEASE THAT RESULTS FROM ACQUIRED GENETIC AND EPIGENETIC ALTERATIONS IN HEMATOPOIETIC PROGENITOR CELLS. DESPITE THE ADVANCES MADE IN UNDERSTANDING THE PATHOGENESIS OF THIS DISEASE, THE OVERALL SURVIVAL OF PATIENTS REMAINS VERY LOW DUE TO THE HIGH RELAPSE RATE. PHARMACOGENETICS AND MASSIVE SEQUENCING STUDIES HAVE ALLOWED THE IDENTIFICATION OF NEW RECURRENT MUTATIONS WITH SIGNIFICANT PROGNOSTIC IMPACT IN AML; FURTHERMORE, IT SEEMS LIKELY THAT WHOLE GENOME SEQUENCING WILL SOON BECOME A STANDARD DIAGNOSTIC TEST, WHICH WILL ALLOW THE MOLECULAR DIAGNOSIS OF PATIENTS. THEREFORE, IT IS NECESSARY TO DEVELOP MOLECULAR TARGETS THAT OPEN NEW THERAPEUTIC PERSPECTIVES AND ALLOW INDIVIDUALIZED TREATMENT OF PATIENTS WITH THIS AGGRESSIVE DISEASE. CHRONIC MYELOID LEUKEMIA (CML) IS THE FIRST NEOPLASTIC DISEASE FOR WHICH A CHARACTERISTIC GENETIC ALTERATION WAS DESCRIBED. IT HAS, BY DEFINITION, A GENETIC MARKER, THE BCR::ABL1 REARRANGEMENT, AS A CONSEQUENCE OF THE T9;22(Q34;Q11) TRANSLOCATION. ITS STUDY IS ESSENTIAL FOR THE DIAGNOSIS OF THIS ENTITY AND ALSO FOR MONITORING THE RESPONSE TO TREATMENT. DRUGS KNOWN AS TYROSINE KINASE INHIBITORS (TKIS) THAT TARGET THE BCR::ABL1 PROTEIN (ORAL TARGETED THERAPY) ARE THE CONVENTIONAL TREATMENT OF CML, REPRESENTING A CHANGE OF PARADIGM IN THE MANAGEMENT OF ONCOHEMATOLOGICAL PATIENTS. 2022 8 230 25 ADAPTIVE AND INNATE CYTOTOXIC EFFECTORS IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) SUBJECTS WITH STABLE DISEASE. CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS CHARACTERISED BY THE EXPANSION OF A NEOPLASTIC MATURE B CELL CLONE. CLL CLINICAL OUTCOME IS VERY HETEROGENEOUS, WITH SOME SUBJECTS NEVER REQUIRING THERAPY AND SOME SHOWING AN AGGRESSIVE DISEASE. GENETIC AND EPIGENETIC ALTERATIONS AND PRO-INFLAMMATORY MICROENVIRONMENT INFLUENCE CLL PROGRESSION AND PROGNOSIS. THE INVOLVEMENT OF IMMUNE-MEDIATED MECHANISMS IN CLL CONTROL NEEDS TO BE INVESTIGATED. WE ANALYSE THE ACTIVATION PROFILE OF INNATE AND ADAPTIVE CYTOTOXIC IMMUNE EFFECTORS IN A COHORT OF 26 CLL PATIENTS WITH STABLE DISEASE, AS KEY ELEMENTS FOR IMMUNE-MEDIATED CONTROL OF CANCER PROGRESSION. WE OBSERVED AN INCREASE IN CD54 EXPRESSION AND INTERFERON (IFN)-GAMMA PRODUCTION BY CYTOTOXIC T CELLS (CTL). CTL ABILITY TO RECOGNISE TUMOUR-TARGETS DEPENDS ON HUMAN LEUKOCYTE ANTIGENS (HLA)-CLASS I EXPRESSION. WE OBSERVED A DECREASED EXPRESSION OF HLA-A AND HLA-BC ON B CELLS OF CLL SUBJECTS, ASSOCIATED WITH A SIGNIFICANT REDUCTION IN INTRACELLULAR CALNEXIN THAT IS RELEVANT FOR HLA SURFACE EXPRESSION. NATURAL KILLER (NK) CELLS AND CTL FROM CLL SUBJECTS SHOW AN INCREASED EXPRESSION OF THE ACTIVATING RECEPTOR KIR2DS2 AND A REDUCTION OF 3DL1 AND NKG2A INHIBITING MOLECULES. THEREFORE, AN ACTIVATION PROFILE CHARACTERISES CTL AND NK CELLS OF CLL SUBJECTS WITH STABLE DISEASE. THIS PROFILE IS CONCEIVABLE WITH THE FUNCTIONAL INVOLVEMENT OF CYTOTOXIC EFFECTORS IN CLL CONTROL. 2023 9 4728 27 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 10 3823 28 INVESTIGATING THE EFFECTS OF A SYNTHETIC CANNABINOID ON THE PATHOGENESIS OF LEUKEMIA AND LEUKEMIC STEM CELLS: A NEW THERAPEUTIC APPROACH. THE POPULARITY AND USAGE OF SYNTHETIC CANNABINOIDS (SCS) ARE INCREASING DUE TO THEIR EASY ACCESSIBILITY AND PSYCHOACTIVE EFFECTS WORLDWIDE. STUDIES ON CANNABINOIDS ON LEUKEMIC STEM CELLS (LSC) AND HEMATOPOIETIC STEM CELLS (HSCS), WHICH ARE THE PRECURSORS OF LEUKEMIA CELLS, GENERALLY DEPEND ON THE NATURAL CANNABINOID DELTA-9-THC. AS THERE IS ONLY A LIMITED NUMBER OF STUDIES FOCUSING ON THE RESULTS OF SC APPLICATIONS, THE REFLECTIONS UPON LSCS HAVE TO BE CLARIFIED. IN THIS STUDY, BIOLOGICAL RESPONSES AND ANTILEUKEMIC EFFECTS OF JWH-018-ONE OF THE FIRST PRODUCED AND WIDELY USED SCS-WERE EVALUATED UPON LEUKEMIA CELLS. WHETHER JWH-018 EXHIBITED A PREVENTIVE EFFECT ON BOTH LEUKEMIC AND HSCS WAS EVALUATED BY PRESENTING A THERAPEUTIC APPROACH FOR THE FIRST TIME IN THE LITERATURE. CELLS WERE ANALYZED IN CASE OF CELL PROLIFERATION, APOPTOSIS, AND TRANSCRIPTIONAL EXPRESSION PROFILING OF SOME SIGNIFICANT JAK/STAT AND AKT/MTOR PATHWAYS, APOPTOTIC, CELL CYCLE REGULATION, AND EPIGENETIC CHROMATIN REMODELING-RELATED GENES FOLLOWING JWH-018 TREATMENT. IN CONCLUSION, HOWEVER, FURTHER STUDIES ARE STILL NEEDED UPON BOTH HSCS AND LSCS TO ILLUMINATE THE EFFECTS OF SCS ON LEUKEMOGENESIS ON CHRONIC MYELOID LEUKEMIA (CML) MORE CLEARLY; WE CONSIDER THAT THE JWH-018 CAN PROVIDE A THERAPEUTIC EFFECT ON THE PATHOGENESIS OF LEUKEMIA AND PARTICULARLY UPON LSCS AND SCS MIGHT HAVE THERAPEUTIC POTENTIAL IN ADDITION TO CURRENT THERAPY. 2022 11 732 30 CANCER DRUG RESISTANCE: THE CENTRAL ROLE OF THE KARYOTYPE. CURRENT GENETIC AND EPIGENETIC THEORIES OF CANCER-SPECIFIC DRUG RESISTANCE DO NOT ADEQUATELY EXPLAIN: (I) THE KARYOTYPIC CHANGES THAT COINCIDE WITH RESISTANCE, (II) THE HIGH RATES AT WHICH CANCER CELLS ACQUIRE AND ENHANCE RESISTANCE COMPARED TO THE RATES OF CONVENTIONAL MUTATION, (III) THE WIDE RANGES OF RESISTANCE SUCH AS MULTIDRUG RESISTANCE, (IV) THE FREQUENT OCCURRENCE OF INTRINSIC DRUG RESISTANCE. WE HAVE RECENTLY PROPOSED, THAT SPECIFIC KARYOTYPIC ALTERATIONS ARE SUFFICIENT FOR DRUG RESISTANCE VIA NEW TRANSCRIPTOMES OF COOPERATIVE GENES, INDEPENDENT OF GENE MUTATION. THIS MECHANISM GENERATES NEW PHENOTYPES JUST LIKE TRISOMY 21 GENERATES DOWN SYNDROME. THESE KARYOTYPIC CHANGES ARE GENERATED BY CANCER-SPECIFIC ANEUPLOIDY AUTOCATALYTICALLY, BECAUSE ANEUPLOIDY DESTABILIZES THE KARYOTYPE BY MISBALANCING TEAMS OF PROTEINS THAT SYNTHESIZE, REPAIR AND SEGREGATE CHROMOSOMES. EVIDENCE FOR THIS CHROMOSOMAL MECHANISM IS AS FOLLOWS: (I) RESISTANCE IS PROPORTIONAL TO THE NUMBER OF CLONAL CHROMOSOMAL ALTERATIONS COMPARED TO DRUG-SENSITIVE PRECURSORS. (II) THE HIGH RATES AT WHICH CANCER CELLS ACQUIRE DRUG RESISTANCE ARE COMPARABLE WITH THE RATES, AS HIGH AS 10(-2) PER CELL GENERATION, AT WHICH THEIR KARYOTYPES CHANGE-DIMMING HOPES FOR GENE-SPECIFIC THERAPIES. (III) MULTIDRUG RESISTANCE PROBABLY REFLECTS UN-SELECTED TRANSCRIPTOMES OF KARYOTYPES SELECTED FOR RESISTANCE AGAINST SPECIFIC DRUGS. (IV) INTRINSIC DRUG RESISTANCE PROBABLY REFLECTS UNSELECTED TRANSCRIPTOMES OF KARYOTYPES SELECTED FOR ONCOGENICITY. WE ALSO ADDUCE EVIDENCE THAT RESISTANCE OF CHRONIC MYELOID LEUKEMIA AGAINST THE DRUG IMATINIB IS CHROMOSOMAL, ALTHOUGH IT IS WIDELY BELIEVED TO BE DUE TO MUTATION OF A KINASE. 2007 12 5899 31 T-CELL DYSFUNCTION IN CHRONIC LYMPHOCYTIC LEUKEMIA FROM AN EPIGENETIC PERSPECTIVE. CELLULAR IMMUNOTHERAPEUTIC APPROACHES SUCH AS CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) THUS FAR HAVE NOT MET THE HIGH EXPECTATIONS. THEREFORE IT IS ESSENTIAL TO BETTER UNDERSTAND THE MOLECULAR MECHANISMS OF CLLINDUCED T-CELL DYSFUNCTION. EVEN THOUGH A SIGNIFICANT NUMBER OF STUDIES ARE AVAILABLE ON T-CELL FUNCTION AND DYSFUNCTION IN CLL PATIENTS, NONE EXAMINE DYSFUNCTION AT THE EPIGENOMIC LEVEL. IN NON-MALIGNANT T-CELL RESEARCH, EPIGENOMICS IS WIDELY EMPLOYED TO DEFINE THE DIFFERENTIATION PATHWAY INTO T-CELL EXHAUSTION. ADDITIONALLY, METABOLIC RESTRICTIONS IN THE TUMOR MICROENVIRONMENT THAT CAUSE T-CELL DYSFUNCTION ARE OFTEN MEDIATED BY EPIGENETIC CHANGES. WITH THIS REVIEW PAPER WE ARGUE THAT UNDERSTANDING THE EPIGENETIC (DYS)REGULATION IN T CELLS OF CLL PATIENTS SHOULD BE LEVELED TO THE KNOWLEDGE WE CURRENTLY HAVE OF THE NEOPLASTIC B CELLS THEMSELVES. THIS WILL PERMIT A COMPLETE UNDERSTANDING OF HOW THESE IMMUNE CELL INTERACTIONS REGULATE T- AND B-CELL FUNCTION. HERE WE RELATE THE CELLULAR AND PHENOTYPIC CHARACTERISTICS OF CLL-INDUCED T-CELL DYSFUNCTION TO EPIGENETIC STUDIES OF T-CELL REGULATION EMERGING FROM CHRONIC VIRAL INFECTION AND TUMOR MODELS. THIS PAPER PROPOSES A FRAMEWORK FOR FUTURE STUDIES INTO THE EPIGENETIC REGULATION OF CLL-INDUCED TCELL DYSFUNCTION, KNOWLEDGE THAT WILL HELP TO GUIDE IMPROVEMENTS IN THE UTILITY OF AUTOLOGOUS T-CELL BASED THERAPIES IN CLL. 2021 13 1682 22 DRUG-MICROENVIRONMENT PERTURBATIONS REVEAL RESISTANCE MECHANISMS AND PROGNOSTIC SUBGROUPS IN CLL. THE TUMOUR MICROENVIRONMENT AND GENETIC ALTERATIONS COLLECTIVELY INFLUENCE DRUG EFFICACY IN CANCER, BUT CURRENT EVIDENCE IS LIMITED AND SYSTEMATIC ANALYSES ARE LACKING. USING CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) AS A MODEL DISEASE, WE INVESTIGATED THE INFLUENCE OF 17 MICROENVIRONMENTAL STIMULI ON 12 DRUGS IN 192 GENETICALLY CHARACTERISED PATIENT SAMPLES. BASED ON MICROENVIRONMENTAL RESPONSE, WE IDENTIFIED FOUR SUBGROUPS WITH DISTINCT CLINICAL OUTCOMES BEYOND KNOWN PROGNOSTIC MARKERS. RESPONSE TO MULTIPLE MICROENVIRONMENTAL STIMULI WAS AMPLIFIED IN TRISOMY 12 SAMPLES. TRISOMY 12 WAS ASSOCIATED WITH A DISTINCT EPIGENETIC SIGNATURE. BROMODOMAIN INHIBITION REVERSED THIS EPIGENETIC PROFILE AND COULD BE USED TO TARGET MICROENVIRONMENTAL SIGNALLING IN TRISOMY 12 CLL. WE QUANTIFIED THE IMPACT OF MICROENVIRONMENTAL STIMULI ON DRUG RESPONSE AND THEIR DEPENDENCE ON GENETIC ALTERATIONS, IDENTIFYING INTERLEUKIN 4 (IL4) AND TOLL-LIKE RECEPTOR (TLR) STIMULATION AS THE STRONGEST ACTUATORS OF DRUG RESISTANCE. IL4 AND TLR SIGNALLING ACTIVITY WAS INCREASED IN CLL-INFILTRATED LYMPH NODES COMPARED WITH HEALTHY SAMPLES. HIGH IL4 ACTIVITY CORRELATED WITH FASTER DISEASE PROGRESSION. THE PUBLICLY AVAILABLE DATASET CAN FACILITATE THE INVESTIGATION OF CELL-EXTRINSIC MECHANISMS OF DRUG RESISTANCE AND DISEASE PROGRESSION. 2022 14 3902 29 LEARNING FROM THE FAILURES OF DRUG DISCOVERY IN B-CELL NON-HODGKIN LYMPHOMAS AND PERSPECTIVES FOR THE FUTURE: CHRONIC LYMPHOCYTIC LEUKEMIA AND DIFFUSE LARGE B-CELL LYMPHOMA AS TWO ENDS OF A SPECTRUM IN DRUG DEVELOPMENT. DESPITE SUBSTANTIAL RECENT ADVANCES, THERE IS STILL AN UNMET NEED FOR BETTER THERAPIES IN B-CELL NON HODGKIN LYMPHOMAS (B-NHL), ESPECIALLY IN RELAPSED OR REFRACTORY DISEASE. MANY NOVEL TARGETED DRUGS HAVE BEEN DEVELOPED BASED ON A BETTER MOLECULAR UNDERSTANDING OF B-NHL. AREAS COVERED: THIS ARTICLE FOCUSES ON CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AS A REPRESENTATIVE FOR INDOLENT LYMPHOMAS AND PARADIGMATIC FOR THE TREMENDOUS PROGRESS IN TREATING B-NHL ON THE ONE HAND AND DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) AS A REPRESENTATIVE FOR AGGRESSIVE LYMPHOMAS AND PARADIGMATIC FOR MANY UNSOLVED PROBLEMS IN LYMPHOMA TREATMENT OR THE OTHER HAND. WE HIGHLIGHT SALIENT POINTS IN CURRENT THERAPIES TARGETING GENETIC, EPIGENETIC, IMMUNOLOGICAL AND MICROENVIRONMENTAL ALTERATIONS. POSSIBLE REASONS FOR DRUG FAILURE IN CLINICAL TRIALS LIKE TUMOR HETEROGENEITY, CLONAL EVOLUTION AND DRUG RESISTANCE MECHANISMS ARE DISCUSSED. BASED THEREON, SOME PERSPECTIVES FOR FURTHER DRUG DISCOVERY ARE GIVEN. EXPERT OPINION: IN VIEW OF THE PATHOGENETIC COMPLEXITY OF LYMPHOMAS, THERAPIES TARGETING EXCLUSIVELY A SINGLE ALTERATION MAY FAIL BECAUSE RESISTANCE MECHANISMS ARE PRESENT EITHER INITIALLY OR EVOLVE DURING TREATMENT. THEREFORE, FUTURE THERAPIES IN B-NHL MAY HAVE TO TARGET THE GREATEST POSSIBLE NUMBER OF GENETIC, IMMUNOLOGICAL OR EPIGENETIC ALTERATIONS STILL ALLOWING TOLERABILITY AND TO MONITOR THESE ALTERATIONS DURING THERAPY. 2017 15 2462 33 EPIGENETIC THERAPY OF MYELODYSPLASTIC SYNDROMES CONNECTS TO CELLULAR DIFFERENTIATION INDEPENDENTLY OF ENDOGENOUS RETROELEMENT DEREPRESSION. BACKGROUND: MYELODYSPLASTIC SYNDROMES (MDS) AND ACUTE MYELOID LEUKAEMIA (AML) ARE CHARACTERISED BY ABNORMAL EPIGENETIC REPRESSION AND DIFFERENTIATION OF BONE MARROW HAEMATOPOIETIC STEM CELLS (HSCS). DRUGS THAT REVERSE EPIGENETIC REPRESSION, SUCH AS 5-AZACYTIDINE (5-AZA), INDUCE HAEMATOLOGICAL IMPROVEMENT IN HALF OF TREATED PATIENTS. ALTHOUGH THE MECHANISMS UNDERLYING THERAPY SUCCESS ARE NOT YET CLEAR, INDUCTION OF ENDOGENOUS RETROELEMENTS (ERES) HAS BEEN HYPOTHESISED. METHODS: USING RNA SEQUENCING (RNA-SEQ), WE COMPARED THE TRANSCRIPTION OF ERES IN BONE MARROW HSCS FROM A NEW COHORT OF MDS AND CHRONIC MYELOMONOCYTIC LEUKAEMIA (CMML) PATIENTS BEFORE AND AFTER 5-AZA TREATMENT WITH HSCS FROM HEALTHY DONORS AND AML PATIENTS. WE FURTHER EXAMINED ERE TRANSCRIPTION USING THE MOST COMPREHENSIVE ANNOTATION OF ERE-OVERLAPPING TRANSCRIPTS EXPRESSED IN HSCS, GENERATED HERE BY DE NOVO TRANSCRIPT ASSEMBLY AND SUPPORTED BY FULL-LENGTH RNA-SEQ. RESULTS: CONSISTENT WITH PRIOR REPORTS, WE FOUND THAT TREATMENT WITH 5-AZA INCREASED THE REPRESENTATION OF ERE-DERIVED RNA-SEQ READS IN THE TRANSCRIPTOME. HOWEVER, SUCH INCREASES WERE COMPARABLE BETWEEN TREATMENT RESPONSES AND FAILURES. THE EXTENDED VIEW OF HSC TRANSCRIPTIONAL DIVERSITY OFFERED BY DE NOVO TRANSCRIPT ASSEMBLY ARGUED AGAINST 5-AZA-RESPONSIVE ERES AS DETERMINANTS OF THE OUTCOME OF THERAPY. INSTEAD, IT UNCOVERED PRE-TREATMENT EXPRESSION AND ALTERNATIVE SPLICING OF DEVELOPMENTALLY REGULATED GENE TRANSCRIPTS AS PREDICTORS OF THE RESPONSE OF MDS AND CMML PATIENTS TO 5-AZA TREATMENT. CONCLUSIONS: OUR STUDY IDENTIFIES THE DEVELOPMENTALLY REGULATED TRANSCRIPTIONAL SIGNATURES OF PROTEIN-CODING AND NON-CODING GENES, RATHER THAN ERES, AS CORRELATES OF A FAVOURABLE RESPONSE OF MDS AND CMML PATIENTS TO 5-AZA TREATMENT AND OFFERS NOVEL CANDIDATES FOR FURTHER EVALUATION. 2019 16 6896 28 [TARGETED EPIGENETIC THERAPY OF CANCER. ACHIEVEMENTS AND PERSPECTIVES]. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL EPIGENETIC CHANGES OF NORMAL CELLS AND CANCER CELLS, AND EMPHASIZE THE ACHIEVEMENTS AND THE PERSPECTIVES OF CANCER EPIGENETIC THERAPY. CANCER EPIGENETIC ALTERATIONS CORRESPOND FOREMOST TO HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES PROMOTORS, GLOBAL DNA HYPOMETHYLATION, AND OVEREXPRESSION AND ACTIVITY OF HISTONE DEACETYLASES. THE PURPOSE OF EPIGENETIC THERAPY IS TO REVERT THE EPIGENETIC ALTERATIONS IN CANCER CELLS AND OBTAIN THE "NORMAL EPIGENOME" RESTORATION. EPIGENETIC TARGETS IN CANCER THERAPY HAVE FOCUSED ON HDACS AND DNMTS INHIBITION. THE AZACITIDINE AND THE DECITABINE, THE VORINOSTAT AND THE ROMIDEPSIN WERE APPROVED BY US-FDA FOR TREATMENT OF MYELODYSPLASTIC SYNDROME, AND CUTANEOUS T-CELL LYMPHOMA, RESPECTIVELY. EPIGENETIC AND EPIGENOMIC CHANGES IN SINGLE OR MULTIPLE GENES HAVE SHOWED POTENTIAL IMPACT IN CANCER AS EARLY DETECTION, PROGNOSIS AND PREDICTIVE MARKS. THE EPIGENETIC REVOLUTION HAS ARRIVED FOR BIOLOGY. THE SIGNIFICANT PROGRESS IN EPIGENETIC STUDIES HAVE ALLOWED US, TO UNDERSTAND NEW LOOKS IN THE PHYSIOLOGY AND PATHOPHYSIOLOGY OF EMBRYONIC DEVELOPMENT, CANCER AND OTHER CHRONIC DISEASES. SPECIFIC MOLECULAR EPIGENETIC ALTERATIONS IN DIFFERENT CANCER TYPES, GIVE US NEW STRATEGIES TO DESIGN IMPROVED CANCER THERAPY. THE CHALLENGE FOR EPIGENETIC INVESTIGATORS IS DESIGN MORE SPECIFIC EPIDRUGS WITH LESSER SIDE EFFECTS. 2012 17 3091 21 GENOMIC AND EPIGENOMIC HETEROGENEITY IN CHRONIC LYMPHOCYTIC LEUKEMIA. DEFINING FEATURES OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ARE NOT ONLY ITS IMMUNOPHENOTYPE OF CD19(+)CD5(+)CD23(+)SIGDIM EXPRESSING CLONAL MATURE B CELLS BUT ALSO ITS HIGHLY VARIABLE CLINICAL COURSE. IN RECENT YEARS, ADVANCES IN MASSIVELY PARALLEL SEQUENCING TECHNOLOGIES HAVE LED TO RAPID PROGRESS IN OUR UNDERSTANDING OF THE CLL GENOME AND EPIGENOME. OVERALL, THESE STUDIES HAVE CLEARLY DEMARCATED NOT ONLY THE VAST DEGREE OF GENETIC AND EPIGENETIC HETEROGENEITY AMONG INDIVIDUALS WITH CLL BUT ALSO EVEN WITHIN INDIVIDUAL PATIENT LEUKEMIAS. WE HEREIN REVIEW THE RAPIDLY GROWING SERIES OF STUDIES ASSESSING THE GENETIC AND EPIGENETIC FEATURES OF CLL WITHIN CLINICALLY DEFINED PERIODS OF ITS GROWTH. THESE STUDIES STRONGLY SUGGEST AN EVOLVING SPECTRUM OF LESIONS OVER TIME AND THAT THESE FEATURES MAY HAVE CLINICAL IMPACT. 2015 18 4545 38 MUTANT P53 GAIN OF FUNCTION AND CHEMORESISTANCE: THE ROLE OF MUTANT P53 IN RESPONSE TO CLINICAL CHEMOTHERAPY. PURPOSE: TO REVIEW MECHANISMS UNDERLYING MUTANT P53 (MUTP53) GAIN OF FUNCTION (GOF) AND MUTP53-INDUCED CHEMORESISTANCE, AND TO INVESTIGATE THE ROLE OF MUTP53 IN RESPONSE TO CLINICAL CHEMOTHERAPY. METHODS: WE SEARCHED THE PUBMED DATABASE FOR CLINICAL STUDIES FROM THE PAST DECADE, INCLUDING DATA EVALUATING THE IMPACT OF MUTP53 IN CLINICAL CHEMOTHERAPY RESPONSE. RESULTS: INTERACTIONS BETWEEN MUTP53 AND TRANSCRIPTIONAL FACTORS, PROTEINS OR DNA STRUCTURES, AS WELL AS EPIGENETIC REGULATION, CONTRIBUTE TO MUTP53 GOF. MAJOR MECHANISMS OF MUTP53-INDUCED CHEMORESISTANCE INCLUDE ENHANCED DRUG EFFLUX AND METABOLISM, PROMOTING SURVIVAL, INHIBITING APOPTOSIS, UPREGULATING DNA REPAIR, SUPPRESSING AUTOPHAGY, ELEVATING MICROENVIRONMENTAL RESISTANCE AND INDUCING A STEM-LIKE PHENOTYPE. CLINICALLY, MUTP53 PREDICTED RESISTANCE TO CHEMOTHERAPY IN DIFFUSE LARGE B-CELL LYMPHOMA, AND ESOPHAGEAL AND OROPHARYNGEAL CANCERS, BUT ITS IMPACT ON CHRONIC LYMPHOCYTIC LEUKEMIA WAS UNCLEAR. IN BLADDER CANCER, MUTP53 DID NOT PREDICT RESISTANCE, WHEREAS IN SOME BREAST AND OVARIAN CANCERS, IT WAS ASSOCIATED WITH SENSITIVITY TO CERTAIN CHEMOTHERAPEUTIC AGENTS. CONCLUSION: MUTP53 HAS AN INTRICATE ROLE IN THE RESPONSE TO CLINICAL CHEMOTHERAPY AND SHOULD NOT BE INTERPRETED IN ISOLATION. FURTHERMORE, WHEN PREDICTING TUMOR RESPONSE TO CHEMOTHERAPY BASED ON THE P53 STATUS, THE DRUGS USED SHOULD ALSO BE TAKEN INTO CONSIDERATION. THESE CONCEPTS REQUIRE FURTHER INVESTIGATION. 2017 19 4320 24 MICRORNAS IN CHRONIC LYMPHOCYTIC LEUKEMIA: AN OLD DISEASE WITH NEW GENETIC INSIGHTS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON LEUKEMIA AMONG ADULT POPULATION IN WESTERN COUNTRY. IN THE LAST DECADE, SEVERAL FINDINGS HAVE SUBSTANTIALLY REVOLUTIONIZED THE OLD CONCEPT THAT CLL IS A DISEASE ORIGINATING FROM MATURE, NOT-DIVIDING CELL WITH INDOLENT CLINICAL COURSE. NOTABLY, NEXT GENERATION SEQUENCING (NGS) HAS CONTRIBUTED TO DEEPEN THE KNOWLEDGE OF THE CELLULAR NETWORKS THAT IMPLY THE ONSET AND THE PROGRESSION OF CLL. AMONG GENETIC ABERRATIONS THAT ARE RECURRENTLY OBSERVED IN B-CELLS FROM PATIENTS WITH CLL, MICRORNA DEREGULATION REPRESENTED THE FIRST EPIGENETIC MECHANISM THAT HAS BEEN IDENTIFIED. THROUGH EPIGENETIC MECHANISM THEY CAN MODULATE GENE EXPRESSION AND INTERFERE WITH CELLULAR PATHWAYS THAT ARE INVOLVED IN CELL CYCLE, APOPTOSIS AND B-CELL RECEPTOR (BCR) ACTIVATION. ALTHOUGH FEW STUDIES HAVE SHOWN THE PROGNOSTIC AND PREDICTIVE VALUE OF MICRORNA EXPRESSION LEVELS, THEIR VALIDATION WITHIN PROSPECTIVE CLINICAL TRIALS IS WARRANTED. 2016 20 2389 32 EPIGENETIC REPOLARIZATION OF T LYMPHOCYTES FROM CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS USING 5-AZA-2'-DEOXYCYTIDINE. T CELL IMMUNE DYSFUNCTION HAS AN IMPORTANT ROLE IN THE PROFOUND IMMUNE SUPPRESSION THAT CHARACTERIZES CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). IMPROPER POLARIZATION OF T CELLS HAS BEEN PROPOSED AS ONE OF THE MECHANISM INVOLVED. MOUNTING DATA IMPLICATES CHROMATIN REGULATION, NAMELY PROMOTER METHYLATION, IN THE PLASTICITY OF NAIVE HUMAN T CELLS. RECENT IN VITRO EVIDENCE INDICATES THAT THIS PLASTICITY MAY BE PHENOTYPICALLY ALTERED BY USING METHYLATION INHIBITORS WHICH ARE APPROVED FOR CLINICAL USE IN CERTAIN TYPES OF CANCER. THESE RESULTS BEG THE QUESTION: CAN THE INEFFECTIVE POLARIZATION OF T LYMPHOCYTES IN THE CONTEXT OF CLL BE EFFECTIVELY MODULATED USING METHYLATION INHIBITORS IN A SUSTAINABLE THERAPEUTIC FASHION? TO ANSWER THIS QUESTION OUR LABORATORY HAS STUDIED THE EFFECTS OF 5-AZA-2'-DEOXYCYTIDINE (5A2) IN HELPER AND CYTOTOXIC T LYMPHOCYTES FROM HEALTHY DONORS AND CLL PATIENTS IN WELL CHARACTERIZED MOLECULAR AND EPIGENETIC SIGNALING PATHWAYS INVOLVED IN EFFECTIVE POLARIZATION. MOREOVER, WE SOUGHT TO INVESTIGATE THE CONSEQUENCES OF METHYLATION INHIBITOR TREATMENT ON LYMPHOCYTE SURVIVAL, ACTIVATION INTENSITY, AND NAIVE CELL POLARIZATION. OUR DATA INDICATES THAT 5A2 TREATMENT CAN DEPOLARIZE TH2 CELLS TO EFFECTIVELY SECRETE INTERFERON GAMMA, SIGNAL VIA T-BET, AND ACHIEVE DEMETHYLATION OF CRITICAL TH1 SPECIFIC PROMOTERS. MOREOVER, WE DEMONSTRATE THAT 5A2 CAN FORCE TH1 POLARIZATION OF NAIVE T CELLS DESPITE A STRONG IL-4 STIMULI AND A LACK OF IL-12. IN CONCLUSION OUR DATA SEEKS TO DEFINE A MODALITY IN WHICH IMPROPER OR INEFFECTIVE T CELL POLARIZATION CAN BE ALTERED BY 5AZA AND COULD BE INCORPORATED IN FUTURE THERAPEUTIC INTERVENTIONS. 2011