1 205 82 ACTIVATION OF HLA-G EXPRESSION BY 5-AZA-2 - DEOXYCYTIDINE IN MALIGNANT HEMATOPOETIC CELLS ISOLATED FROM LEUKEMIA PATIENTS. HUMAN LEUKOCYTE ANTIGEN - G (HLA-G) IS A NON-CLASSICAL HLA CLASS I ANTIGEN WITH RESTRICTED DISTRIBUTION IN NORMAL TISSUES. ECTOPIC HLA-G EXPRESSION OBSERVED AT SOME PATHOLOGICAL CIRCUMSTANCES AS MALIGNANT TRANSFORMATION MIGHT BE TRIGGERED BY EPIGENETIC MODIFICATIONS SUCH AS DNA DEMETHYLATION. RECENTLY IT WAS DEMONSTRATED THAT DNA METHYLTRANSFERASE INHIBITOR 5-AZA-2 - DEOXYCYTIDINE (ADC) INDUCES/ENHANCES HLA-G TRANSCRIPTION IN MANY LEUKEMIA CELL LINES OF DIFFERENT ORIGIN. HERE WE INVESTIGATED THE EFFECT OF ADC ON HLA-G EXPRESSION IN MALIGNANT HEMATOPOETIC CELLS ISOLATED FROM PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) AND CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL). WE DETECTED HLA-G EXPRESSION IN UNTREATED CELLS FROM SOME PATIENTS. NEVERTHELESS TREATMENT WITH 5-AZA-2 - DEOXYCYTIDINE ENHANCED HLA-G TRANSCRIPTION AND CONCOMITANTLY HLA-G PROTEIN SYNTHESIS IN SOME LEUKEMIA CELLS. 2009 2 1078 24 CLONAL NON-MALIGNANT HEMATOLOGICAL DISORDERS: UNRAVELING MOLECULAR PATHOGENIC MECHANISMS TO DEVELOP NOVEL TARGETED THERAPEUTICS. CLONAL NON-MALIGNANT HEMATOLOGICAL DISORDERS ARE A HETEROGENEOUS GROUP OF DISEASES THAT ARE PARTICULARLY CHALLENGING FOR HEMATOLOGISTS. INDEED, MOST OBVIOUS AND FREQUENT HEMATOLOGICAL DISEASES INCLUDE A BROAD SPECTRUM OF MALIGNANCIES, SUCH AS LEUKEMIAS, LYMPHOMAS, MYELOMA, AND OTHER MYELOPROLIFERATIVE OR LYMPHOPROLIFERATIVE DISORDERS. IN RECENT YEARS, ALL THESE DISEASES HAVE BEEN CATEGORIZED BY THE WHO ACCORDING TO A NOVEL CLASSIFICATION OF MYELOID AND LYMPHOID MALIGNANCIES, WHICH TAKES IN ACCOUNT THE OUTSTANDING PROGRESS IN OUR UNDERSTANDING OF MOLECULAR DEFECTS UNDERLYING HEMATOLOGICAL MALIGNANCIES. REGARDLESS OF A NUMBER OF NOVEL TECHNOLOGIES, HEMATOLOGISTS CONTINUE TO DEAL DAILY WITH CONDITIONS WHERE A CLEAR DIAGNOSIS OF A MALIGNANCY IS MISSING: THIS IS THE CASE OF SEVERAL CLONAL HEMATOLOGICAL DISORDERS, WHICH ARE CONSIDERED BONA FIDE NON-MALIGNANT. SOME MYELODYSPLASTIC SYNDROMES, CHRONIC T AND NK DISORDERS OF GRANULAR LYMPHOCYTES, MYELOFIBROSIS, MONOCLONAL GAMMOPATHIES, MONOCLONAL B-CEL LYMPHOCYTOSIS, MASTOCYTOSIS AND PAROXYSMAL NOCTURNAL HEMOGLOBINURIA ARE PARADIGMATIC EXAMPLES OF HOW CLONAL DISORDERS ARE CLEARLY DIFFERENT FROM CANCERS, EVEN IF THEY MAY SHARE WITH HEMATOLOGICAL MALIGNANCIES SIMILAR MOLECULAR, GENETIC, EPIGENETIC AND IMMUNOLOGICAL PROCESSES. INDEED, IT IS NOT ENTIRELY CLEAR WHETHER IN INDIVIDUAL CONDITIONS SUCH PATHOGENIC MECHANISMS MAY REPRESENT INITIAL STEP(S) OF MALIGNANT TRANSFORMATION, MAKING A BRIDGE BETWEEN THESE CLONAL NON-MALIGNANT DISORDERS AND TYPICAL HEMATOLOGICAL CANCERS. SOME OF THESE NON-MALIGNANT DISORDERS IMPLY SPECIFIC PATHOGENIC MECHANISMS AND/OR CLINICAL COURSE, AND SO THEY HAVE BEEN DEFINITELY ESTABLISHED WITH THEIR OWN BIOLOGICAL AND CLINICAL IDENTITY. HOWEVER, THE OBVIOUS QUESTION WHETHER SOME OF THESE CLONAL NON-MALIGNANT HEMATOLOGICAL DISEASES FORM SOME A KIND OF DISEASE-CONTINUUM WITH THEIR CORRESPONDING MALIGNANT COUNTERPART IS STILL TO BE ANSWERED. 2014 3 4760 28 NOVEL TREATMENTS OF ADULT T CELL LEUKEMIA LYMPHOMA. ADULT T CELL LEUKEMIA-LYMPHOMA (ATL) IS AN AGGRESSIVE MALIGNANCY SECONDARY TO CHRONIC INFECTION WITH THE HUMAN T CELL LEUKEMIA VIRUS TYPE I (HTLV-I) RETROVIRUS. ATL CARRIES A DISMAL PROGNOSIS. ATL CLASSIFIES INTO FOUR SUBTYPES (ACUTE, LYMPHOMA, CHRONIC, AND SMOLDERING) WHICH DISPLAY DIFFERENT CLINICAL FEATURES, PROGNOSIS AND RESPONSE TO THERAPY, HENCE REQUIRING DIFFERENT CLINICAL MANAGEMENT. SMOLDERING AND CHRONIC SUBTYPES RESPOND WELL TO ANTIRETROVIRAL THERAPY USING THE COMBINATION OF ZIDOVUDINE (AZT) AND INTERFERON-ALPHA (IFN) WITH A SIGNIFICANT PROLONGATION OF SURVIVAL. CONVERSELY, THE WATCH AND WAIT STRATEGY OR CHEMOTHERAPY FOR THESE INDOLENT SUBTYPES ALLIES WITH A POOR LONG-TERM OUTCOME. ACUTE ATL IS ASSOCIATED WITH CHEMO-RESISTANCE AND DISMAL PROGNOSIS. LYMPHOMA SUBTYPES RESPOND BETTER TO INTENSIVE CHEMOTHERAPY BUT SURVIVAL REMAINS POOR. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) RESULTS IN LONG-TERM SURVIVAL IN ROUGHLY ONE THIRD OF TRANSPLANTED PATIENTS BUT ONLY A SMALL PERCENTAGE OF PATIENTS CAN MAKE IT TO TRANSPLANT. OVERALL, CURRENT TREATMENTS OF AGGRESSIVE ATL ARE NOT SATISFACTORY. PROGNOSIS OF REFRACTORY OR RELAPSED PATIENTS IS DISMAL WITH SOME ENCOURAGING RESULTS WHEN USING LENALIDOMIDE OR MOGAMULIZUMAB. TO OVERCOME RESISTANCE AND PREVENT RELAPSE, PRECLINICAL OR PILOT CLINICAL STUDIES USING TARGETED THERAPIES SUCH AS ARSENIC/IFN, MONOCLONAL ANTIBODIES, EPIGENETIC THERAPIES ARE PROMISING BUT WARRANT FURTHER CLINICAL INVESTIGATION. ANTI-ATL VACCINES INCLUDING TAX PEPTIDE-PULSED DENDRITIC CELLS, INDUCED TAX-SPECIFIC CTL RESPONSES IN ATL PATIENTS. FINALLY, BASED ON THE PROGRESS IN UNDERSTANDING THE PATHOPHYSIOLOGY OF ATL, AND THE RISK-ADAPTED TREATMENT APPROACHES TO DIFFERENT ATL SUBTYPES, TREATMENT STRATEGIES OF ATL SHOULD TAKE INTO ACCOUNT THE HOST IMMUNE RESPONSES AND THE HOST MICROENVIRONMENT INCLUDING HTLV-1 INFECTED NON-MALIGNANT CELLS. HEREIN, WE WILL PROVIDE A SUMMARY OF NOVEL TREATMENTS OF ATL IN VITRO, IN VIVO, AND IN EARLY CLINICAL TRIALS. 2020 4 939 23 CHRONIC LYMPHOCYTIC LEUKEMIA AND 13Q14: MIRS AND MORE. LOSS OF A CRITICAL REGION IN 13Q14.3 [DEL(13Q)] IS THE MOST COMMON GENOMIC ABERRATION IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), OCCURRING IN MORE THAN 50% OF PATIENTS (STILGENBAUER ET AL., ONCOGENE 1998;16:1891 - 1897, DOHNER ET AL., N ENGL J MED 2000;343:1910 - 1916). DESPITE EXTENSIVE INVESTIGATIONS, NO POINT MUTATIONS HAVE BEEN FOUND IN THE REMAINING ALLELE THAT WOULD INACTIVATE ONE OF THE CANDIDATE TUMOR SUPPRESSOR GENES AND EXPLAIN THE PATHOMECHANISM POSTULATED FOR THIS REGION. HOWEVER, THE GENES IN THE REGION ARE SIGNIFICANTLY DOWN-REGULATED IN CLL CELLS, MORE THAN WOULD BE EXPECTED BY GENE DOSAGE, AND RECENTLY A COMPLEX EPIGENETIC REGULATORY MECHANISM WAS IDENTIFIED FOR 13Q14.3 IN NON-MALIGNANT CELLS THAT INVOLVES ASYNCHRONOUS REPLICATION TIMING AND MONOALLELIC EXPRESSION OF CANDIDATE TUMOR SUPPRESSOR GENES. HERE, WE PROPOSE A MODEL OF A MULTIGENIC PATHOMECHANISM IN 13Q14.3, WHERE SEVERAL TUMOR SUPPRESSOR GENES, INCLUDING THE MIRNA GENES MIR-16-1 AND MIR-15A, ARE CO-REGULATED BY THE TWO LONG NON-CODING RNA GENES DLEU1 AND DLEU2 THAT SPAN THE CRITICAL REGION. FURTHERMORE, WE PROPOSE THESE CO-REGULATED GENES TO BE INVOLVED IN THE SAME MOLECULAR PATHWAYS, THEREBY ALSO FORMING A FUNCTIONAL GENE CLUSTER. ELUCIDATING THE MOLECULAR AND CELLULAR FUNCTION OF THE 13Q14.3 CANDIDATE GENES WILL SHED LIGHT ON THE UNDERLYING PATHOMECHANISM OF CLL. 2009 5 1533 26 DNA METHYLATION DYNAMICS DURING B CELL MATURATION UNDERLIE A CONTINUUM OF DISEASE PHENOTYPES IN CHRONIC LYMPHOCYTIC LEUKEMIA. CHARTING DIFFERENCES BETWEEN TUMORS AND NORMAL TISSUE IS A MAINSTAY OF CANCER RESEARCH. HOWEVER, CLONAL TUMOR EXPANSION FROM COMPLEX NORMAL TISSUE ARCHITECTURES POTENTIALLY OBSCURES CANCER-SPECIFIC EVENTS, INCLUDING DIVERGENT EPIGENETIC PATTERNS. USING WHOLE-GENOME BISULFITE SEQUENCING OF NORMAL B CELL SUBSETS, WE OBSERVED BROAD EPIGENETIC PROGRAMMING OF SELECTIVE TRANSCRIPTION FACTOR BINDING SITES COINCIDENT WITH THE DEGREE OF B CELL MATURATION. BY COMPARING NORMAL B CELLS TO MALIGNANT B CELLS FROM 268 PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), WE SHOWED THAT TUMORS DERIVE LARGELY FROM A CONTINUUM OF MATURATION STATES REFLECTED IN NORMAL DEVELOPMENTAL STAGES. EPIGENETIC MATURATION IN CLL WAS ASSOCIATED WITH AN INDOLENT GENE EXPRESSION PATTERN AND INCREASINGLY FAVORABLE CLINICAL OUTCOMES. WE FURTHER UNCOVERED THAT MOST PREVIOUSLY REPORTED TUMOR-SPECIFIC METHYLATION EVENTS ARE NORMALLY PRESENT IN NON-MALIGNANT B CELLS. INSTEAD, WE IDENTIFIED A POTENTIAL PATHOGENIC ROLE FOR TRANSCRIPTION FACTOR DYSREGULATION IN CLL, WHERE EXCESS PROGRAMMING BY EGR AND NFAT WITH REDUCED EBF AND AP-1 PROGRAMMING IMBALANCES THE NORMAL B CELL EPIGENETIC PROGRAM. 2016 6 5462 19 RESEARCH PROGRESS ON EPIGENETICS OF SMALL B-CELL LYMPHOMA. SMALL B-CELL LYMPHOMA IS THE CLASSIFICATION OF B-CELL CHRONIC LYMPHOPROLIFERATIVE DISORDERS THAT INCLUDE CHRONIC LYMPHOCYTIC LEUKAEMIA/SMALL LYMPHOCYTIC LYMPHOMA, FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA. THE CLINICAL PRESENTATION IS SOMEWHAT HETEROGENEOUS, AND ITS OCCURRENCE AND DEVELOPMENT MECHANISMS ARE NOT YET PRECISE AND MAY INVOLVE EPIGENETIC CHANGES. EPIGENETIC ALTERATIONS MAINLY INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA, WHICH ARE ESSENTIAL FOR GENETIC DETECTION, EARLY DIAGNOSIS, AND ASSESSMENT OF TREATMENT RESISTANCE IN SMALL B-CELL LYMPHOMA. AS CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA HAS ALREADY BEEN REPORTED IN THE LITERATURE, THIS ARTICLE FOCUSES ON SMALL B-CELL LYMPHOMAS SUCH AS FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, AND WALDENSTROM MACROGLOBULINEMIA. IT DISCUSSES RECENT DEVELOPMENTS IN EPIGENETIC RESEARCH TO DIAGNOSE AND TREAT THIS GROUP OF LYMPHOMAS. THIS REVIEW PROVIDES NEW IDEAS FOR THE TREATMENT AND PROGNOSIS ASSESSMENT OF SMALL B-CELL LYMPHOMA BY EXPLORING THE CONNECTION BETWEEN SMALL B-CELL LYMPHOMA AND EPIGENETICS. 2022 7 4595 24 NATURAL KILLER CELLS AND IMMUNE-CHECKPOINT INHIBITOR THERAPY: CURRENT KNOWLEDGE AND NEW CHALLENGES. THE DISCOVERY OF IMMUNE CHECKPOINTS (ICS) AND THE DEVELOPMENT OF SPECIFIC BLOCKERS TO RELIEVE IMMUNE EFFECTOR CELLS FROM THIS INHIBITING MECHANISM HAS CHANGED THE VIEW OF ANTI-CANCER THERAPY. IN ADDITION TO CYTOTOXIC T LYMPHOCYTE ANTIGEN 4 (CTLA4) AND PROGRAMMED DEATH 1 (PD1), CLASSICAL ICS OF T LYMPHOCYTES AND RECENTLY DESCRIBED ALSO ON A FRACTION OF NATURAL KILLER (NK) CELLS, SEVERAL NK CELL RECEPTORS, INCLUDING KILLER IMMUNOGLOBULIN-LIKE INHIBITORY RECEPTORS (KIRS) AND NGK2A, HAVE BEEN RECOGNIZED AS CHECKPOINT MEMBERS TYPICAL OF THE NK CELL POPULATION. THIS OFFERS THE OPPORTUNITY OF A DUAL-CHECKPOINT INHIBITION APPROACH, TARGETING CLASSICAL AND NON-CLASSICAL ICS AND LEADING TO A SYNERGISTIC THERAPEUTIC EFFECT. IN THIS REVIEW, WE WILL OVERVIEW AND DISCUSS THIS NEW PERSPECTIVE, FOCUSING ON THE MOST RELEVANT CANDIDATES FOR THIS ROLE AMONG THE VARIETY OF POTENTIAL NK ICS. BESIDE LISTING AND DEFINING CLASSICAL ICS EXPRESSED ALSO BY NK CELLS, OR NON-CLASSICAL ICS EITHER ON T OR ON NK CELLS, WE WILL ADDRESS THEIR ROLE IN NK CELL SURVIVAL, CHRONIC STIMULATION OR FUNCTIONAL EXHAUSTION, AND THE POTENTIAL RELEVANCE OF THIS PHENOMENON ON ANTI-TUMOR IMMUNE RESPONSE. FURTHERMORE, NK ICS WILL BE PROPOSED AS POSSIBLE NEW TARGETS FOR THE DEVELOPMENT OF EFFICIENT COMBINED IMMUNOTHERAPY, NOT FORGETTING THE RELEVANT CONCERNS THAT MAY BE RAISED ON NK IC BLOCKADE. FINALLY, THE IMPACT OF EPIGENETIC DRUGS IN SUCH A COMPLEX THERAPEUTIC PICTURE WILL BE BRIEFLY ADDRESSED. 2022 8 1657 24 DOWN-EXPRESSION OF MIR-152 LEAD TO IMPAIRED ANTI-TUMOR EFFECT OF NK VIA UPREGULATION OF HLA-G. IT IS KNOWN THAT CHRONIC HBV INFECTION (CHB) IS THE MAJOR RISK FACTOR FOR HEPATOCELLULAR CARCINOMA (HCC) BECAUSE CHB COULD NOT ONLY CAUSE LIVER TUMORIGENESIS BUT ALSO LEAD TO CHANGE OF LOCAL MICROENVIROMENT AND LOWER IMMUNE RESPONSE TO INFECTED AND CANCEROUS CELLS (IMMUNE TOLERANCE). HUMAN LEUCOCYTE ANTIGEN-G (HLA-G) BELONGS TO A NON-CLASSIC MHC-I FAMILY AND WAS CONSIDERED TO BE AN IMMUNE TOLERANCE MOLECULE, WHICH COULD BIND TO IMMUNOSUPPRESSIVE RECEPTORS OF NATURAL KILLER CELL (NK) AND T CELLS AND TRIGGER IMMUNOSUPPRESSIVE SIGNALING. RECENTLY, NUMEROUS STUDIES HIGHLIGHTED THAT MICRORNAS (MIRNAS) WERE SIGNIFICANTLY DIFFERENTIALLY EXPRESSED IN HCC TUMORIGENESIS, AND THE EXPRESSION WAS TISSUE-SPECIFIC, INDICATING THAT MIRNAS MAY CAUSE GREAT EPIGENETIC CHANGES IN HCC TUMORIGENESIS. IN THIS STUDY, WE FOUND THAT THE EXPRESSION OF HLA-G WAS UPREGULATED BY HEPATITIS B VIRUS (HBV) INFECTION AND MIR-152; A HLA-G-TARGETING MIRNA WAS DOWNREGULATED BY HBV INFECTION. AND HIGH EXPRESSION OF HLA-G FURTHER SUPPRESSED NK AGAINST CANCER CELLS, PROVIDING A NEW CONCEPT THAT MIR-152 WAS INVOLVED IN HBV-INDUCED HEPATOCELLULAR CARCINOMA. 2016 9 941 25 CHRONIC LYMPHOCYTIC LEUKEMIA B-CELL NORMAL CELLULAR COUNTERPART: CLUES FROM A FUNCTIONAL PERSPECTIVE. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY THE CLONAL EXPANSION OF SMALL MATURE-LOOKING CD19+ CD23+ CD5+ B-CELLS THAT ACCUMULATE IN THE BLOOD, BONE MARROW, AND LYMPHOID ORGANS. TO DATE, NO CONSENSUS HAS BEEN REACHED CONCERNING THE NORMAL CELLULAR COUNTERPART OF CLL B-CELLS AND SEVERAL B-CELL TYPES HAVE BEEN PROPOSED. CLL B-CELLS HAVE REMARKABLE PHENOTYPIC AND GENE EXPRESSION PROFILE HOMOGENEITY. IN RECENT YEARS, THE MOLECULAR AND CELLULAR BIOLOGY OF CLL HAS BEEN ENRICHED BY SEMINAL INSIGHTS THAT ARE LEADING TO A BETTER UNDERSTANDING OF THE NATURAL HISTORY OF THE DISEASE. IMMUNOPHENOTYPIC AND MOLECULAR APPROACHES (INCLUDING IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE GENE MUTATIONAL STATUS, TRANSCRIPTIONAL AND EPIGENETIC PROFILING) COMPARING THE NORMAL B-CELL SUBSET AND CLL B-CELLS PROVIDE SOME NEW INSIGHTS INTO THE NORMAL CELLULAR COUNTERPART. FUNCTIONAL CHARACTERISTICS (INCLUDING ACTIVATION REQUIREMENTS AND PROPENSITY FOR PLASMA CELL DIFFERENTIATION) OF CLL B-CELLS HAVE NOW BEEN INVESTIGATED FOR 50 YEARS. B-CELL SUBSETS DIFFER SUBSTANTIALLY IN TERMS OF THEIR FUNCTIONAL FEATURES. ANALYSIS OF SHARED FUNCTIONAL CHARACTERISTICS MAY REVEAL SIMILARITIES BETWEEN NORMAL B-CELL SUBSETS AND CLL B-CELLS, ALLOWING SPECULATIVE ASSIGNMENT OF A NORMAL CELLULAR COUNTERPART FOR CLL B-CELLS. IN THIS REVIEW, WE SUMMARIZE CURRENT DATA REGARDING PERIPHERAL B-CELL DIFFERENTIATION AND HUMAN B-CELL SUBSETS AND SUGGEST POSSIBILITIES FOR A NORMAL CELLULAR COUNTERPART BASED ON THE FUNCTIONAL CHARACTERISTICS OF CLL B-CELLS. HOWEVER, A DEFINITIVE NORMAL CELLULAR COUNTERPART CANNOT BE ATTRIBUTED ON THE BASIS OF THE AVAILABLE DATA. WE DISCUSS THE FUNCTIONAL CHARACTERISTICS REQUIRED FOR A CELL TO BE LOGICALLY CONSIDERED TO BE THE NORMAL COUNTERPART OF CLL B-CELLS. 2018 10 4432 19 MOLECULAR CHARACTERIZATION OF RICHTER SYNDROME IDENTIFIES DE NOVO DIFFUSE LARGE B-CELL LYMPHOMAS WITH POOR PROGNOSIS. RICHTER SYNDROME (RS) IS THE TRANSFORMATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) INTO AGGRESSIVE LYMPHOMA, MOST COMMONLY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). WE CHARACTERIZE 58 PRIMARY HUMAN RS SAMPLES BY GENOME-WIDE DNA METHYLATION AND WHOLE-TRANSCRIPTOME PROFILING. OUR COMPREHENSIVE APPROACH DETERMINES RS DNA METHYLATION PROFILE AND UNRAVELS A CLL EPIGENETIC IMPRINT, ALLOWING CLL-RS CLONAL RELATIONSHIP ASSESSMENT WITHOUT THE NEED OF THE INITIAL CLL TUMOR DNA. DNA METHYLATION- AND TRANSCRIPTOMIC-BASED CLASSIFIERS WERE DEVELOPED, AND TESTING ON LANDMARK DLBCL DATASETS IDENTIFIES A POOR-PROGNOSIS, ACTIVATED B-CELL-LIKE DLBCL SUBSET IN 111/1772 SAMPLES. THE CLASSIFICATION ROBUSTLY IDENTIFIES PHENOTYPES VERY SIMILAR TO RS WITH A SPECIFIC GENOMIC PROFILE, ACCOUNTING FOR 4.3-8.3% OF DE NOVO DLBCLS. IN THIS WORK, RS MULTI-OMICS CHARACTERIZATION DETERMINES ONCOGENIC MECHANISMS, ESTABLISHES A SURROGATE MARKER FOR CLL-RS CLONAL RELATIONSHIP, AND PROVIDES A CLINICALLY RELEVANT CLASSIFIER FOR A SUBSET OF PRIMARY "RS-TYPE DLBCL" WITH UNFAVORABLE PROGNOSIS. 2023 11 230 30 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 12 3298 21 HIGH-DEFINITION CPG METHYLATION OF NOVEL GENES IN GASTRIC CARCINOGENESIS IDENTIFIED BY NEXT-GENERATION SEQUENCING. GASTRIC CANCERS ARE THE MOST FREQUENT GASTRIC MALIGNANCY AND USUALLY ARISE IN THE SEQUENCE OF HELICOBACTER PYLORI-ASSOCIATED CHRONIC GASTRITIS. CPG METHYLATION IS A CENTRAL MECHANISM OF EPIGENETIC GENE REGULATION AFFECTING CANCER-RELATED GENES, AND OCCURS EARLY IN GASTRIC CARCINOGENESIS. DNA SAMPLES FROM NON-METAPLASTIC GASTRIC MUCOSA WITH VARIABLE LEVELS OF GASTRITIS (NON-METAPLASTIC MUCOSA), INTESTINAL METAPLASIA, OR GASTRIC CANCER WERE SCREENED WITH METHYLATION ARRAYS FOR CPG METHYLATION OF CANCER-RELATED GENES AND 30 GENE TARGETS WERE FURTHER CHARACTERIZED BY HIGH-DEFINITION BISULFITE NEXT-GENERATION SEQUENCING. IN ADDITION, DATA FROM THE CANCER GENOME ATLAS WERE ANALYZED FOR CORRELATION OF METHYLATION WITH GENE EXPRESSION. OVERALL, 13 GENES HAD SIGNIFICANTLY INCREASED CPG METHYLATION IN GASTRIC CANCER VS NON-METAPLASTIC MUCOSA (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, AND SNRPN). FURTHER, MOST OF THESE GENES HAD CORRESPONDING REDUCED EXPRESSION LEVELS IN GASTRIC CANCER COMPARED WITH INTESTINAL METAPLASIA, INCLUDING NOVEL HYPERMETHYLATED GENES IN GASTRIC CANCER (FLI1, GALR1, SGCE, AND SNRPN), SUGGESTING THAT THEY MAY REGULATE NEOPLASTIC TRANSFORMATION FROM NON-MALIGNANT INTESTINAL METAPLASIA TO CANCER. OUR DATA SUGGEST A TUMOR-SUPPRESSOR ROLE FOR FLI1 IN GASTRIC CANCER, CONSISTENT WITH RECENTLY REPORTED DATA IN BREAST CANCER. FOR THE GENES WITH STRONGEST METHYLATION/EXPRESSION CORRELATION, NAMELY FLI1, THE EXPRESSION WAS LOWEST IN MICROSATELLITE-UNSTABLE TUMORS COMPARED WITH OTHER GASTRIC CANCER MOLECULAR SUBTYPES. IMPORTANTLY, REDUCED EXPRESSION OF HYPERMETHYLATED BRINP1 AND SGCE WAS SIGNIFICANTLY ASSOCIATED WITH FAVORABLE SURVIVAL IN GASTRIC CANCER. IN SUMMARY, WE REPORT NOVEL METHYLATION GENE TARGETS THAT MAY HAVE FUNCTIONAL ROLES IN DISCRETE STAGES OF GASTRIC CARCINOGENESIS AND MAY SERVE AS BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS OF GASTRIC CANCER. 2016 13 5512 14 RICHTER SYNDROME IN CHRONIC LYMPHOCYTIC LEUKEMIA: UPDATES ON BIOLOGY, CLINICAL FEATURES AND THERAPY. RICHTER SYNDROME (RS) OR RICHTER TRANSFORMATION IS THE DEVELOPMENT OF SECONDARY AGGRESSIVE LYMPHOMA IN THE SETTING OF UNDERLYING CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA (CLL/SLL). MOST FREQUENTLY CLL TRANSFORMS INTO DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) (90%) AND RARELY (10%) INTO HODGKIN LYMPHOMA, TERMED HODGKIN VARIANT OF RICHTER SYNDROME (HVRS). RS IS GENERALLY CHARACTERIZED BY AN AGGRESSIVE CLINICAL COURSE AND POOR PROGNOSIS. IN RECENT YEARS, MAJOR ADVANCES HAVE BEEN MADE IN UNDERSTANDING GENETIC EVENTS WHICH RELATE TO THE PROGRESSION OF CLL OR TRANSFORMATION INTO RS. BETTER UNDERSTANDING OF THE MOLECULAR PATHWAYS HAS REVEALED THAT RS IS NOT A SINGLE HOMOGENEOUS ENTITY. THE MAJORITY OF CASES ARE CLONALLY RELATED TO THE ORIGINAL CLL CLONE, WHILE A MINORITY DEVELOP FROM AN UNRELATED CLONE. THIS REVIEW SUMMARIZES NEW DATA RELATING TO THE MOLECULAR BIOLOGY AND THE GENETIC/EPIGENETIC CHANGES OCCURRING DURING RICHTER TRANSFORMATION, AND ALSO CONSIDERS THE CLINICAL FEATURES AND THERAPY FOR BOTH DLBCL-RS AND HODGKIN VARIANT-RS. 2015 14 1467 22 DISTINCT CLINICAL AND GENETIC FEATURES OF HEPATITIS B VIRUS-ASSOCIATED FOLLICULAR LYMPHOMA IN CHINESE PATIENTS. HEPATITIS B VIRUS (HBV) INFECTION HAS BEEN ASSOCIATED WITH AN INCREASED RISK FOR B-CELL LYMPHOMAS. WE PREVIOUSLY SHOWED THAT 20% OF DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) PATIENTS FROM CHINA, AN ENDEMIC AREA OF HBV INFECTION, HAVE CHRONIC HBV INFECTION (SURFACE ANTIGEN-POSITIVE, HBSAG+) AND ARE CHARACTERIZED BY DISTINCT CLINICAL AND GENETIC FEATURES. HERE, WE SHOWED THAT 24% OF FOLLICULAR LYMPHOMA (FL) CHINESE PATIENTS ARE HBSAG+. COMPARED WITH THE HBSAG- FL PATIENTS, HBSAG+ PATIENTS ARE YOUNGER, HAVE A HIGHER HISTOLOGICAL GRADE AT DIAGNOSIS, AND HAVE A HIGHER INCIDENCE OF DISEASE PROGRESSION WITHIN 24 MONTHS. MOREOVER, BY SEQUENCING THE GENOMES OF 109 FL TUMORS, WE OBSERVED ENHANCED MUTAGENESIS AND DISTINCT GENETIC PROFILE IN HBSAG+ FLS, WITH A UNIQUE SET OF PREFERENTIALLY MUTATED GENES (TNFAIP3, FAS, HIST1H1C, KLF2, TP53, PIM1, TMSB4X, DUSP2, TAGAP, LYN, AND SETD2) BUT LACK OF THE HALLMARK OF HBSAG- FLS (IE, IGH/BCL2 TRANSLOCATIONS AND CREBBP MUTATIONS). TRANSCRIPTOMIC ANALYSES FURTHER SHOWED THAT HBSAG+ FLS DISPLAYED GENE-EXPRESSION SIGNATURES RESEMBLING THE ACTIVATED B-CELL-LIKE SUBTYPE OF DIFFUSE LARGE B-CELL LYMPHOMA, INVOLVING IRF4-TARGETED GENES AND NF-KAPPAB/MYD88 SIGNALING PATHWAYS. FINALLY, WE IDENTIFIED AN INCREASED INFILTRATION OF CD8+ MEMORY T CELLS, CD4+ TH1 CELLS, AND M1 MACROPHAGES AND HIGHER T-CELL EXHAUSTION GENE SIGNATURE IN HBSAG+ FL SAMPLES. TAKEN TOGETHER, WE PRESENT NEW GENETIC/EPIGENETIC EVIDENCE THAT LINKS CHRONIC HBV INFECTION TO B-CELL LYMPHOMAGENESIS, AND HBV-ASSOCIATED FL IS LIKELY TO HAVE A DISTINCT CELL-OF-ORIGIN AND REPRESENT AS A SEPARATE SUBTYPE OF FL. TARGETABLE GENETIC/EPIGENETIC ALTERATIONS IDENTIFIED IN TUMORS AND THEIR ASSOCIATED TUMOR MICROENVIRONMENT MAY PROVIDE POTENTIAL NOVEL THERAPEUTIC APPROACHES FOR THIS SUBGROUP OF PATIENTS. 2022 15 4446 23 MOLECULAR MAP OF CHRONIC LYMPHOCYTIC LEUKEMIA AND ITS IMPACT ON OUTCOME. RECENT ADVANCES IN CANCER CHARACTERIZATION HAVE CONSISTENTLY REVEALED MARKED HETEROGENEITY, IMPEDING THE COMPLETION OF INTEGRATED MOLECULAR AND CLINICAL MAPS FOR EACH MALIGNANCY. HERE, WE FOCUS ON CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), A B CELL NEOPLASM WITH VARIABLE NATURAL HISTORY THAT IS CONVENTIONALLY CATEGORIZED INTO TWO SUBTYPES DISTINGUISHED BY EXTENT OF SOMATIC MUTATIONS IN THE HEAVY-CHAIN VARIABLE REGION OF IMMUNOGLOBULIN GENES (IGHV). TO BUILD THE 'CLL MAP,' WE INTEGRATED GENOMIC, TRANSCRIPTOMIC AND EPIGENOMIC DATA FROM 1,148 PATIENTS. WE IDENTIFIED 202 CANDIDATE GENETIC DRIVERS OF CLL (109 NEW) AND REFINED THE CHARACTERIZATION OF IGHV SUBTYPES, WHICH REVEALED DISTINCT GENOMIC LANDSCAPES AND LEUKEMOGENIC TRAJECTORIES. DISCOVERY OF NEW GENE EXPRESSION SUBTYPES FURTHER SUBCATEGORIZED THIS NEOPLASM AND PROVED TO BE INDEPENDENT PROGNOSTIC FACTORS. CLINICAL OUTCOMES WERE ASSOCIATED WITH A COMBINATION OF GENETIC, EPIGENETIC AND GENE EXPRESSION FEATURES, FURTHER ADVANCING OUR PROGNOSTIC PARADIGM. OVERALL, THIS WORK REVEALS FRESH INSIGHTS INTO CLL ONCOGENESIS AND PROGNOSTICATION. 2022 16 5899 29 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 17 940 19 CHRONIC LYMPHOCYTIC LEUKEMIA AND MANTLE CELL LYMPHOMA: CROSSROADS OF GENETIC AND MICROENVIRONMENT INTERACTIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND MANTLE CELL LYMPHOMA (MCL) ARE 2 WELL-DEFINED ENTITIES THAT DIVERGE IN THEIR BASIC PATHOGENIC MECHANISMS AND CLINICAL EVOLUTION BUT THEY SHARE EPIDEMIOLOGICAL CHARACTERISTICS, CELLS OF ORIGIN, MOLECULAR ALTERATIONS, AND CLINICAL FEATURES THAT DIFFER FROM OTHER LYMPHOID NEOPLASMS. CLL AND MCL ARE CLASSICALLY CONSIDERED INDOLENT AND AGGRESSIVE NEOPLASMS, RESPECTIVELY. HOWEVER, THE CLINICAL EVOLUTION OF BOTH TUMORS IS VERY HETEROGENEOUS, WITH SUBSETS OF PATIENTS HAVING STABLE DISEASE FOR A LONG TIME WHEREAS OTHERS REQUIRE IMMEDIATE INTERVENTION. BOTH CLL AND MCL INCLUDE 2 MAJOR MOLECULAR SUBTYPES THAT SEEM TO DERIVE FROM ANTIGEN-EXPERIENCED CD5(+) B CELLS THAT RETAIN A NAIVE OR MEMORY-LIKE EPIGENETIC SIGNATURE AND CARRY A VARIABLE LOAD OF IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE REGION SOMATIC MUTATIONS FROM TRULY UNMUTATED TO HIGHLY MUTATED, RESPECTIVELY. THESE 2 SUBTYPES OF TUMORS DIFFER IN THEIR MOLECULAR PATHWAYS, GENOMIC ALTERATIONS, AND CLINICAL BEHAVIOR, BEING MORE AGGRESSIVE IN NAIVE-LIKE THAN MEMORY-LIKE-DERIVED TUMORS IN BOTH CLL AND MCL. THE PATHOGENESIS OF THE 2 ENTITIES INTEGRATES THE RELEVANT INFLUENCE OF B-CELL RECEPTOR SIGNALING, TUMOR CELL MICROENVIRONMENT INTERACTIONS, GENOMIC ALTERATIONS, AND EPIGENOME MODIFICATIONS THAT CONFIGURE THE EVOLUTION OF THE TUMORS AND OFFER NEW POSSIBILITIES FOR THERAPEUTIC INTERVENTION. THIS REVIEW WILL FOCUS ON THE SIMILARITIES AND DIFFERENCES OF THESE 2 TUMORS BASED ON RECENT STUDIES THAT ARE ENHANCING THE UNDERSTANDING OF THEIR PATHOGENESIS AND CREATING SOLID BASES FOR NEW MANAGEMENT STRATEGIES. 2018 18 3475 27 IDENTIFICATION OF A STAT5 TARGET GENE, DPF3, PROVIDES NOVEL INSIGHTS IN CHRONIC LYMPHOCYTIC LEUKEMIA. STAT5 CONTROLS ESSENTIAL CELLULAR FUNCTIONS AND IS ENCODED BY TWO GENES, STAT5A AND STAT5B. TO PROVIDE INSIGHT TO THE MECHANISMS LINKING HEMATOLOGIC MALIGNANCY TO STAT5 ACTIVATION/REGULATION OF TARGET GENES, WE IDENTIFIED STAT5 TARGET GENES AND FOCUSED ON DPF3 GENE, WHICH ENCODES FOR AN EPIGENETIC FACTOR. DPF3 EXPRESSION WAS INDUCED UPON IL-3 STIMULATION IN BA/F3 CELLS, WHILE STRONG BINDING OF BOTH STAT5A AND STAT5B WAS DETECTED IN ITS PROMOTER. REDUCED EXPRESSION OF DPF3 WAS DETECTED IN BA/F3 CELLS WITH STAT5A AND STAT5B KNOCK-DOWN, SUGGESTING THAT THIS GENE IS POSITIVELY REGULATED BY STAT5, UPON IL-3 STIMULATION. FURTHERMORE, THIS GENE WAS SIGNIFICANTLY UP-REGULATED IN CLL PATIENTS, WHERE DPF3 GENE/PROTEIN UP-REGULATION AND STRONG STAT5 BINDING TO THE DPF3 PROMOTER, CORRELATED WITH INCREASED STAT5 ACTIVATION, MAINLY IN NON-MALIGNANT MYELOID CELLS (GRANULOCYTES). OUR FINDINGS PROVIDE INSIGHTS IN THE STAT5 DEPENDENT TRANSCRIPTIONAL REGULATION OF DPF3, AND DEMONSTRATE FOR THE FIRST TIME INCREASED STAT5 ACTIVATION IN GRANULOCYTES OF CLL PATIENTS. NOVEL ROUTES OF INVESTIGATION ARE OPENED TO FACILITATE THE UNDERSTANDING OF THE ROLE OF STAT5 ACTIVATION IN THE COMMUNICATION BETWEEN NON-MALIGNANT MYELOID AND MALIGNANT B-CELLS, AND THE FUNCTIONS OF STAT5 TARGET GENES NETWORKS IN CLL BIOLOGY. 2013 19 5141 18 POTENTIAL RELEVANCE OF B-CELL MATURATION PATHWAYS IN DEFINING THE CELL(S) OF ORIGIN FOR CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A COMMON, INCURABLE DISEASE OF UNDEFINED CAUSE. NOTABLY, THE NORMAL CELL EQUIVALENTS OF CLL CELLS REMAIN ELUSIVE, AND IT IS POSSIBLE THAT THE DISEASE EMANATES FROM SEVERAL NORMAL B-CELL SUBSETS. THIS ARTICLE REVIEWS THE LITERATURE RELATING TO THIS ISSUE, FOCUSING ON RECENT FINDINGS, IN PARTICULAR MADE THROUGH EPIGENETIC ANALYSES THAT STRONGLY SUPPORT THE DISEASE DEVELOPING FROM A NORMAL AG-EXPERIENCED AND MEMORY CELL-LIKE B LYMPHOCYTE. IT ALSO REPORTS THE KNOWN PATHWAYS WHEREBY NORMAL B LYMPHOCYTES MATURE AFTER ANTIGENIC CHALLENGE AND PROPOSES THAT THIS INFORMATION IS RELEVANT IN DEFINING THE CELLS OF ORIGIN OF THIS DISEASE. 2021 20 6307 21 THE REFERENCE EPIGENOME AND REGULATORY CHROMATIN LANDSCAPE OF CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A FREQUENT HEMATOLOGICAL NEOPLASM IN WHICH UNDERLYING EPIGENETIC ALTERATIONS ARE ONLY PARTIALLY UNDERSTOOD. HERE, WE ANALYZE THE REFERENCE EPIGENOME OF SEVEN PRIMARY CLLS AND THE REGULATORY CHROMATIN LANDSCAPE OF 107 PRIMARY CASES IN THE CONTEXT OF NORMAL B CELL DIFFERENTIATION. WE IDENTIFY THAT THE CLL CHROMATIN LANDSCAPE IS LARGELY INFLUENCED BY DISTINCT DYNAMICS DURING NORMAL B CELL MATURATION. BEYOND THIS, WE DEFINE EXTENSIVE CATALOGUES OF REGULATORY ELEMENTS DE NOVO REPROGRAMMED IN CLL AS A WHOLE AND IN ITS MAJOR CLINICO-BIOLOGICAL SUBTYPES CLASSIFIED BY IGHV SOMATIC HYPERMUTATION LEVELS. WE UNCOVER THAT IGHV-UNMUTATED CLLS HARBOR MORE ACTIVE AND OPEN CHROMATIN THAN IGHV-MUTATED CASES. FURTHERMORE, WE SHOW THAT DE NOVO ACTIVE REGIONS IN CLL ARE ENRICHED FOR NFAT, FOX AND TCF/LEF TRANSCRIPTION FACTOR FAMILY BINDING SITES. ALTHOUGH MOST GENETIC ALTERATIONS ARE NOT ASSOCIATED WITH CONSISTENT EPIGENETIC PROFILES, CLLS WITH MYD88 MUTATIONS AND TRISOMY 12 SHOW DISTINCT CHROMATIN CONFIGURATIONS. FURTHERMORE, WE OBSERVE THAT NON-CODING MUTATIONS IN IGHV-MUTATED CLLS ARE ENRICHED IN H3K27AC-ASSOCIATED REGULATORY ELEMENTS OUTSIDE ACCESSIBLE CHROMATIN. OVERALL, THIS STUDY PROVIDES AN INTEGRATIVE PORTRAIT OF THE CLL EPIGENOME, IDENTIFIES EXTENSIVE NETWORKS OF ALTERED REGULATORY ELEMENTS AND SHEDS LIGHT ON THE RELATIONSHIP BETWEEN THE GENETIC AND EPIGENETIC ARCHITECTURE OF THE DISEASE. 2018