1 5462 87 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 2 2992 36 GENETIC LANDSCAPE AND DEREGULATED PATHWAYS IN B-CELL LYMPHOID MALIGNANCIES. WITH THE INTRODUCTION OF NEXT-GENERATION SEQUENCING, THE GENETIC LANDSCAPE OF THE COMPLEX GROUP OF B-CELL LYMPHOID MALIGNANCIES HAS RAPIDLY BEEN UNRAVELLED IN RECENT YEARS. THIS HAS PROVIDED IMPORTANT INFORMATION ABOUT RECURRENT GENETIC EVENTS AND IDENTIFIED KEY PATHWAYS DEREGULATED IN EACH LYMPHOMA SUBTYPE. IN PARALLEL, THERE HAS BEEN INTENSE SEARCH AND DEVELOPMENT OF NOVEL TYPES OF TARGETED THERAPY THAT 'HIT' CENTRAL MECHANISMS IN LYMPHOMA PATHOBIOLOGY, SUCH AS BTK, PI3K OR BCL2 INHIBITORS. IN THIS REVIEW, WE WILL OUTLINE THE CURRENT VIEW OF THE GENETIC LANDSCAPE OF SELECTED ENTITIES: FOLLICULAR LYMPHOMA, DIFFUSE LARGE B-CELL LYMPHOMA, MANTLE CELL LYMPHOMA, CHRONIC LYMPHOCYTIC LEUKAEMIA AND MARGINAL ZONE LYMPHOMA. WE WILL DETAIL RECURRENT ALTERATIONS AFFECTING IMPORTANT SIGNALLING PATHWAYS, THAT IS THE B-CELL RECEPTOR/NF-KAPPAB PATHWAY, NOTCH SIGNALLING, JAK-STAT SIGNALLING, P53/DNA DAMAGE RESPONSE, APOPTOSIS AND CELL CYCLE REGULATION, AS WELL AS OTHER PERHAPS UNEXPECTED CELLULAR PROCESSES, SUCH AS IMMUNE REGULATION, CELL MIGRATION, EPIGENETIC REGULATION AND RNA PROCESSING. WHILST MANY OF THESE PATHWAYS/PROCESSES ARE COMMONLY ALTERED IN DIFFERENT LYMPHOID TUMORS, ALBEIT AT VARYING FREQUENCIES, OTHERS ARE PREFERENTIALLY TARGETED IN SELECTED B-CELL MALIGNANCIES. SOME OF THESE GENETIC LESIONS ARE EITHER INVOLVED IN DISEASE ONTOGENY OR LINKED TO THE EVOLUTION OF EACH DISEASE AND/OR SPECIFIC CLINICOBIOLOGICAL FEATURES, AND SOME OF THEM HAVE BEEN DEMONSTRATED TO HAVE PROGNOSTIC AND EVEN PREDICTIVE IMPACT. FUTURE WORK IS ESPECIALLY NEEDED TO UNDERSTAND THE THERAPY-RESISTANT DISEASE, PARTICULARLY IN PATIENTS TREATED WITH TARGETED THERAPY, AND TO IDENTIFY NOVEL TARGETS AND THERAPEUTIC STRATEGIES IN ORDER TO REALIZE TRUE PRECISION MEDICINE IN THIS CLINICALLY HETEROGENEOUS PATIENT GROUP. 2017 3 940 30 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 4 147 38 ABERRANT EPIGENETIC GENE REGULATION IN LYMPHOID MALIGNANCIES. IN LYMPHOID MALIGNANCIES, ABERRANT EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION AND HISTONE MODIFICATIONS INFLUENCE CHROMATIN ARCHITECTURE AND CAN RESULT IN ALTERED GENE EXPRESSION. THESE ALTERATIONS COMMONLY AFFECT GENES THAT PLAY IMPORTANT ROLES IN THE CELL CYCLE, APOPTOSIS, AND DNA REPAIR IN NON-HODGKIN LYMPHOMA (NHL). THE ABILITY TO IDENTIFY EPIGENETIC MODIFICATIONS TO THESE IMPORTANT GENES HAS INCREASED EXPONENTIALLY DUE TO ADVANCES IN TECHNOLOGY. AS A RESULT, THERE ARE WELL-DEFINED, GENE-SPECIFIC EPIGENETIC ABERRATIONS ASSOCIATED WITH NHL COMPRISING FOLLICULAR LYMPHOMA (FL), MANTLE CELL LYMPHOMA (MCL), CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), AND DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL). THE IDENTIFICATION OF THESE GENES IS IMPORTANT BECAUSE THEY MAY BE USED AS BIOMARKERS FOR PROGNOSIS, DIAGNOSIS AND IN DEVELOPING IMPROVED TREATMENT STRATEGIES. ALSO IMPORTANT, IN THE CONTROL OF GENE EXPRESSION, IS THE PACKAGING OF DNA WITHIN THE NUCLEUS OF A CELL. THIS PACKAGING CAN BE DISTORTED BY EPIGENETIC ALTERATIONS AND MAY ALTER THE ACCESSIBILITY OF CERTAIN REGIONS OF THE GENOME IN CANCER CELLS. THIS REVIEW DISCUSSES THE IMPACT OF KNOWN EPIGENETIC ABERRATION ON THE REGULATION OF GENE EXPRESSION IN NHL AND PROVIDES INSIGHT INTO THE SPATIAL CONFORMATION OF THE GENOME (DNA PACKAGING) IN ACUTE LYMPHOBLASTIC LEUKEMIA. 2013 5 4693 22 NEXT GENERATION OF TARGETED MOLECULES FOR NON-HODGKIN LYMPHOMAS: SMALL-MOLECULE INHIBITORS OF INTRACELLULAR TARGETS AND SIGNALING PATHWAYS. ADVANCES IN OUR UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF B-CELL LYMPHOMA HAVE GUIDED THE DEVELOPMENT OF TARGETED THERAPIES THAT DISRUPT ABERRANT SIGNALING PATHWAYS IMPORTANT FOR COMMUNICATION WITHIN LYMPHOMA CELLS AND FOR THEIR INTERACTIONS WITH THE TUMOR MICROENVIRONMENT. THIS HAS LED TO UNPRECEDENTED THERAPEUTIC PROGRESS, WITH BIOLOGIC AGENTS THAT HAVE BEGUN TO TRANSFORM THE CARE OF PATIENTS WITH LYMPHOMA AND CHRONIC LYMPHOCYTIC LEUKEMIA. THIS REVIEW DISCUSSES THE MECHANISMS OF ACTION, CLINICAL DEVELOPMENT, AND EMERGING APPLICATIONS OF SMALL-MOLECULE INHIBITORS THAT TARGET B-CELL RECEPTOR SIGNALING PATHWAYS, B-CELL LYMPHOMA-2 INHIBITORS, SELECTIVE INHIBITORS OF NUCLEAR EXPORT, AND EPIGENETIC MODIFIERS. 2016 6 4320 22 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 7 941 27 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 8 2652 32 EPIGENOMICS OF LEUKEMIA: FROM MECHANISMS TO THERAPEUTIC APPLICATIONS. LEUKEMOGENESIS IS A MULTISTEP PROCESS IN WHICH SUCCESSIVE TRANSFORMATIONAL EVENTS ENHANCE THE ABILITY OF A CLONAL POPULATION ARISING FROM HEMATOPOIETIC PROGENITOR CELLS TO PROLIFERATE, DIFFERENTIATE AND SURVIVE. CLINICALLY AND PATHOLOGICALLY, LEUKEMIA IS SUBDIVIDED INTO FOUR MAIN CATEGORIES: CHRONIC LYMPHOCYTIC LEUKEMIA, CHRONIC MYELOID LEUKEMIA, ACUTE LYMPHOCYTIC LEUKEMIA AND ACUTE MYELOID LEUKEMIA. LEUKEMIA HAS BEEN PREVIOUSLY CONSIDERED ONLY AS A GENETIC DISEASE. HOWEVER, IN RECENT YEARS, SIGNIFICANT ADVANCES HAVE BEEN MADE IN THE ELUCIDATION OF THE LEUKEMOGENESIS-ASSOCIATED PROCESSES. THUS, WE HAVE COME TO UNDERSTAND THAT EPIGENETIC ALTERATIONS INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS AND MIRNA ARE INVOLVED IN THE PERMANENT CHANGES OF GENE EXPRESSION CONTROLLING THE LEUKEMIA PHENOTYPE. IN THIS ARTICLE, WE WILL FOCUS ON THE EPIGENETIC DEFECTS ASSOCIATED WITH LEUKEMIA AND THEIR IMPLICATIONS AS BIOMARKERS FOR DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC APPLICATIONS. 2011 9 937 18 CHRONIC LYMPHOCYTIC LEUKAEMIA GENOMICS AND THE PRECISION MEDICINE ERA. MASSIVE GENOMIC ANALYSES HAVE UNDERSCORED THE DIVERSITY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) BETWEEN PATIENTS. GENETIC HETEROGENEITY OF TUMOUR CLONES WITHIN A PATIENT MAY FUEL TUMOUR EVOLUTION. SEVERAL RECURRENTLY DEREGULATED INTRA-CELLULAR PATHWAYS ARE CANDIDATES FOR TARGETED THERAPIES THAT ARE VERY PROMISING AND ARE DRAMATICALLY CHANGING CLINICAL PATIENTS' PERSPECTIVES. IN THIS REVIEW WE PRESENT AN OVERVIEW OF THE GENETIC AND EPIGENETIC FEATURES OF CLL AND THEIR CLINICAL AND BIOLOGICAL IMPLICATIONS. 2017 10 2857 25 FROM PATHOGENESIS TO TREATMENT OF CHRONIC LYMPHOCYTIC LEUKAEMIA. CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) HAS SEVERAL UNIQUE FEATURES THAT DISTINGUISH IT FROM OTHER CANCERS. MOST CLL TUMOUR CELLS ARE INERT AND ARRESTED IN G0/G1 OF THE CELL CYCLE AND THERE IS ONLY A SMALL PROLIFERATIVE COMPARTMENT; HOWEVER, THE PROGRESSIVE ACCUMULATION OF MALIGNANT CELLS WILL ULTIMATELY LEAD TO SYMPTOMATIC DISEASE. PATHOGENIC MECHANISMS HAVE BEEN ELUCIDATED THAT INVOLVE MULTIPLE EXTERNAL (FOR EXAMPLE, MICROENVIRONMENTAL STIMULI AND ANTIGENIC DRIVE) AND INTERNAL (GENETIC AND EPIGENETIC) EVENTS THAT ARE CRUCIAL IN THE TRANSFORMATION, PROGRESSION AND EVOLUTION OF CLL. OUR GROWING UNDERSTANDING OF CLL BIOLOGY IS ALLOWING THE TRANSLATION OF TARGETS AND BIOLOGICAL CLASSIFIERS INTO CLINICAL PRACTICE. 2010 11 3091 20 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 12 5141 21 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 13 4481 26 MOLECULAR PROFILING OF CHRONIC LYMPHOCYTIC LEUKAEMIA: GENETICS MEETS EPIGENETICS TO IDENTIFY PREDISPOSING GENES. MOLECULAR PROFILING MAY LEAD TO A BETTER UNDERSTANDING OF A DISEASE. THIS KNOWLEDGE IS ESPECIALLY IMPORTANT IN MALIGNANCIES, WHERE MULTIPLE ALTERATIONS ARE REQUIRED DURING THE PROGRESSION FROM PREMALIGNANT TO MALIGNANT STAGES. SUCH INFORMATION CAN BE USEFUL FOR THE DEVELOPMENT OF NOVEL BIOMARKERS THAT ALLOW THE PREDICTION OF A CLINICAL COURSE, RESPONSE TO TREATMENT OR EARLY DETECTION. MOLECULAR DATA IS ALSO UTILIZED TO DEVELOP TARGETED THERAPIES. MOREOVER, GENE DEFECTS IDENTIFIED IN PROFILING STUDIES WILL HELP TO UNDERSTAND THE MOLECULAR PATHWAYS DISRUPTED IN THE DISEASE. THIS REVIEW PROVIDES AN OVERVIEW OF MOLECULAR PROFILING APPROACHES IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). WE WILL DESCRIBE OUR CURRENT UNDERSTANDING OF GENETIC ALTERATIONS IN CLL, THE USE OF FAMILIAL CLL FOR THE IDENTIFICATION OF PREDISPOSING MUTATIONS, AND THE SEARCH FOR EPIGENETIC ALTERATIONS IN CLL. 2007 14 944 27 CHRONIC LYMPHOCYTIC LEUKEMIA: FROM MOLECULAR PATHOGENESIS TO NOVEL THERAPEUTIC STRATEGIES. CHRONIC LYMPHOCYTIC LEUKEMIA IS A WELL-DEFINED LYMPHOID NEOPLASM WITH VERY HETEROGENEOUS BIOLOGICAL AND CLINICAL BEHAVIOR. THE LAST DECADE HAS BEEN REMARKABLY FRUITFUL IN NOVEL FINDINGS ELUCIDATING MULTIPLE ASPECTS OF THE PATHOGENESIS OF THE DISEASE INCLUDING MECHANISMS OF GENETIC SUSCEPTIBILITY, INSIGHTS INTO THE RELEVANCE OF IMMUNOGENETIC FACTORS DRIVING THE DISEASE, PROFILING OF GENOMIC ALTERATIONS, EPIGENETIC SUBTYPES, GLOBAL EPIGENOMIC TUMOR CELL REPROGRAMMING, MODULATION OF TUMOR CELL AND MICROENVIRONMENT INTERACTIONS, AND DYNAMICS OF CLONAL EVOLUTION FROM EARLY STEPS IN MONOCLONAL B CELL LYMPHOCYTOSIS TO PROGRESSION AND TRANSFORMATION INTO DIFFUSE LARGE B-CELL LYMPHOMA. ALL THIS KNOWLEDGE HAS OFFERED NEW PERSPECTIVES THAT ARE BEING EXPLOITED THERAPEUTICALLY WITH NOVEL TARGET AGENTS AND MANAGEMENT STRATEGIES. IN THIS REVIEW WE PROVIDE AN OVERVIEW OF THESE NOVEL ADVANCES AND HIGHLIGHT QUESTIONS AND PERSPECTIVES THAT NEED FURTHER PROGRESS TO TRANSLATE INTO THE CLINICS THE BIOLOGICAL KNOWLEDGE AND IMPROVE THE OUTCOME OF THE PATIENTS. 2020 15 2944 30 GENETIC AND EPIGENETIC BASIS OF CHRONIC LYMPHOCYTIC LEUKEMIA. PURPOSE OF REVIEW: NEXT-GENERATION SEQUENCING OF WHOLE GENOMES, EXOMES AND DNA METHYLOMES IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAS PROVIDED THE FIRST COMPREHENSIVE VIEW OF SOMATIC MUTATIONS AND METHYLATION CHANGES IN THIS DISEASE. THIS REVIEW SUMMARIZES THE RECENT FINDINGS IN THIS FIELD AND THEIR IMPACT ON OUR CURRENT UNDERSTANDING OF THIS NEOPLASM. RECENT FINDINGS: GENOMIC STUDIES HAVE REVEALED A REMARKABLE MOLECULAR HETEROGENEITY OF THE DISEASE, WITH ONLY FEW GENES MUTATED IN UP TO 10-15% OF THE PATIENTS AND A RELATIVELY LARGE NUMBER OF GENES RECURRENTLY MUTATED AT LOW FREQUENCY. THE MUTATED GENES TEND TO CLUSTER IN DIFFERENT PATHWAYS THAT INCLUDE NOTCH1 SIGNALING, RNA SPLICING, PROCESSING AND TRANSPORT MACHINERY, INNATE INFLAMMATORY RESPONSE, AND DNA DAMAGE AND CELL CYCLE CONTROL, AMONG OTHERS. NOTCH1 AND SF3B1 MUTATIONS ARE EMERGING AS NEW DRIVERS OF AGGRESSIVE FORMS OF THE DISEASE. GENOME-WIDE METHYLATION STUDIES HAVE SHOWN THAT CLL TRANSFORMATION IS ASSOCIATED WITH A MASSIVE HYPOMETHYLATION PHENOMENON FREQUENTLY AFFECTING THE ENHANCER REGIONS. THIS EPIGENETIC REPROGRAMMING MAINTAINS AN IMPRINT OF THE PUTATIVE CELL OF ORIGIN FROM NAIVE AND MEMORY B-CELLS. SUMMARY: GENOMIC AND EPIGENOMIC STUDIES OF CLL ARE RESHAPING OUR UNDERSTANDING OF THE DISEASE AND PROVIDE NEW PERSPECTIVE FOR A MORE INDIVIDUALIZED DIAGNOSIS AND NEW POTENTIAL THERAPEUTIC TARGETS. 2013 16 3015 28 GENETICS AND EPIGENETICS OF CLL. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAS A HETEROGENEOUS BIOLOGICAL BEHAVIOR, WHICH IS HIGHLY INFLUENCED BY ITS IMMUNOGENETIC, EPIGENETIC, AND GENOMIC PROPERTIES. THE REMARKABLY VARIABLE CLINICAL COURSE OF THE DISEASE HAS BEEN ASSOCIATED WITH GENETIC FEATURES SUCH AS CHROMOSOMAL ABNORMALITIES, THE PRESENCE OF EITHER HIGH OR LOW NUMBERS OF SOMATIC HYPERMUTATIONS (SHM) IN THE VARIABLE REGION OF THE IMMUNOGLOBULIN HEAVY CHAIN LOCUS (IGHV), AND SOMATIC MUTATIONS OF SEVERAL SPECIFIC DRIVER GENES. NEXT-GENERATION SEQUENCING (NGS) TECHNOLOGIES HAVE PROVIDED A COMPREHENSIVE CHARACTERIZATION OF THE GENOMIC AND EPIGENOMIC LANDSCAPE IN CLL, ELUCIDATING IMPORTANT UNDERLYING MECHANISMS OF THE DISEASE'S BIOLOGY. THE SCOPE OF THIS REVIEW IS TO SUMMARIZE THE MOST RECENT DISCOVERIES ABOUT NOVEL GENETIC AND EPIGENETIC ALTERATIONS, DISCUSSING THEIR IMPACT ON CLINICAL OUTCOMES AND RESPONSE TO CURRENTLY AVAILABLE THERAPY. 2023 17 557 32 B-CELL ANTIGEN RECEPTOR SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA: THERAPEUTIC TARGETS AND TRANSLATIONAL OPPORTUNITIES. B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY CLONALLY EXPANDED AND MOLECULARLY HETEROGENEOUS POPULATIONS OF B LYMPHOCYTES WITH IMPAIRED APOPTOTIC MECHANISMS. THIS OCCURS AS A RESULT OF MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES, INCLUDING CHROMOSOMAL ABERRATIONS AND ENHANCER REGION HYPOMETHYLATION, OFTEN IMPINGING ON INTRACELLULAR SIGNALING PATHWAYS THAT ARE ESSENTIAL TO NORMAL B-CELL ACTIVATION, PROLIFERATION, AND SURVIVAL. THE B-CELL ANTIGEN RECEPTOR (BCR) SIGNALING IS ONE SUCH PATHWAY USURPED BY MALIGNANT B CELLS, AS EXEMPLIFIED BY THE EARLY PHASE CLINICAL SUCCESS ACHIEVED BY SMALL-MOLECULE AGENTS TARGETING KEY PLAYERS INVOLVED IN THE PATHWAY. SUCH NEW TARGETED AGENTS, INCLUDING THOSE THAT INHIBIT THE FUNCTION OF SPLEEN TYROSINE KINASE (SYK), BRUTON'S TYROSINE KINASE (BTK), PHOSPHATIDYLINOSITOL 3-KINASES (PI3K), AND B-CELL LYMPHOMA 2 (BCL-2), ALONG WITH THE CURRENT STANDARD THERAPY COMPRISING CHEMO-IMMUNOTHERAPIES WITH OR WITHOUT B-CELL DEPLETING BIOLOGIC AGENT RITUXIMAB (ANTI-CD20 MONOCLONAL ANTIBODY), SHOULD EXPAND THE ARMAMENTARIUM FOR CLL THERAPY. WE REVIEW THE THERAPEUTIC AGENTS CURRENTLY IN CLINICAL DEVELOPMENT WHICH TARGET DIFFERENT EFFECTORS OF THE MALIGNANT BCR SIGNALING, AND DISCUSS THEIR OVERLAPPING AND DISCRIMINATING TRANSLATIONAL OPPORTUNITIES IN THE CONTEXT OF CLL TREATMENT. 2013 18 945 27 CHRONIC LYMPHOCYTIC LEUKEMIA: MOLECULAR HETEROGENEITY REVEALED BY HIGH-THROUGHPUT GENOMICS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAS BEEN CONSISTENTLY AT THE FOREFRONT OF GENETIC RESEARCH OWING TO ITS PREVALENCE AND THE ACCESSIBILITY OF SAMPLE MATERIAL. RECENTLY, GENOME-WIDE TECHNOLOGIES HAVE BEEN INTENSIVELY APPLIED TO CLL GENETICS, WITH REMARKABLE PROGRESS. SINGLE NUCLEOTIDE POLYMORPHISM ARRAYS HAVE IDENTIFIED RECURRING CHROMOSOMAL ABERRATIONS, THEREBY FOCUSING FUNCTIONAL STUDIES ON DISCRETE GENOMIC LESIONS AND LEADING TO THE FIRST IMPLICATION OF SOMATIC MICRORNA DISRUPTION IN CANCER. NEXT-GENERATION SEQUENCING (NGS) HAS FURTHER TRANSFORMED OUR UNDERSTANDING OF CLL BY IDENTIFYING NOVEL RECURRENTLY MUTATED PUTATIVE DRIVERS, INCLUDING THE UNEXPECTED DISCOVERY OF SOMATIC MUTATIONS AFFECTING SPLICEOSOME FUNCTION. NGS HAS FURTHER ENABLED IN-DEPTH EXAMINATION OF THE TRANSCRIPTIONAL AND EPIGENETIC CHANGES IN CLL THAT ACCOMPANY GENETIC LESIONS, AND HAS SHED LIGHT ON HOW DIFFERENT DRIVER EVENTS APPEAR AT DIFFERENT STAGES OF DISEASE PROGRESSION AND CLONALLY EVOLVE WITH RELAPSED DISEASE. IN ADDITION TO PROVIDING IMPORTANT INSIGHTS INTO DISEASE BIOLOGY, THESE DISCOVERIES HAVE SIGNIFICANT TRANSLATIONAL POTENTIAL. THEY ENHANCE PROGNOSIS BY HIGHLIGHTING SPECIFIC LESIONS ASSOCIATED WITH POOR CLINICAL OUTCOMES (FOR EXAMPLE, DRIVER EVENTS SUCH AS MUTATIONS IN THE SPLICING FACTOR SUBUNIT GENE SF3B1) OR WITH INCREASED CLONAL HETEROGENEITY (FOR EXAMPLE, THE PRESENCE OF SUBCLONAL DRIVER MUTATIONS). HERE, WE REVIEW NEW GENOMIC DISCOVERIES IN CLL AND DISCUSS THEIR POSSIBLE IMPLICATIONS IN THE ERA OF PRECISION MEDICINE. 2013 19 4473 28 MOLECULAR PATHOGENESIS OF CLL AND ITS EVOLUTION. IN SPITE OF BEING THE MOST PREVALENT ADULT LEUKEMIA IN WESTERN COUNTRIES, THE MOLECULAR MECHANISMS DRIVING THE ESTABLISHMENT AND PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) REMAIN LARGELY UNKNOWN. IN RECENT YEARS, THE USE OF NEXT-GENERATION SEQUENCING TECHNIQUES HAS UNCOVERED NEW AND, IN SOME CASES, UNEXPECTED DRIVER GENES WITH PROGNOSTIC AND THERAPEUTIC VALUE. THE MUTATIONAL LANDSCAPE OF CLL IS CHARACTERIZED BY HIGH-GENETIC AND EPIGENETIC HETEROGENEITY, LOW MUTATION RECURRENCE AND A LONG TAIL OF CASES WITH UNDEFINED DRIVER GENES. ON THE OTHER HAND, THE USE OF DEEP SEQUENCING HAS ALSO REVEALED HIGH INTRA-TUMOR HETEROGENEITY AND PROVIDED A DETAILED PICTURE OF CLONAL EVOLUTION PROCESSES. THIS PHENOMENON, IN WHICH ABERRANT DNA METHYLATION CAN ALSO PARTICIPATE, APPEARS TO BE TIGHTLY ASSOCIATED TO POOR OUTCOMES AND CHEMO-REFRACTORINESS, THUS PROVIDING A NEW SUBJECT FOR THERAPEUTIC INTERVENTION. HENCE, AND HAVING IN MIND THE LIMITATIONS DERIVED FROM THE CLL COMPLEXITY THUS DESCRIBED, THE APPLICATION OF MASSIVELY PARALLEL SEQUENCING STUDIES HAS UNVEILED A WEALTH OF INFORMATION THAT IS EXPECTED TO SUBSTANTIALLY IMPROVE PATIENT STAGING SCHEMES AND CLL CLINICAL MANAGEMENT. 2015 20 5687 29 SIGNIFICANCE OF INACTIVATED GENES IN LEUKEMIA: PATHOGENESIS AND PROGNOSIS. EPIGENETIC AND GENETIC ALTERATIONS ARE TWO MECHANISMS PARTICIPATING IN LEUKEMIA, WHICH CAN INACTIVATE GENES INVOLVED IN LEUKEMIA PATHOGENESIS OR PROGRESSION. THE PURPOSE OF THIS REVIEW WAS TO INTRODUCE VARIOUS INACTIVATED GENES AND EVALUATE THEIR POSSIBLE ROLE IN LEUKEMIA PATHOGENESIS AND PROGNOSIS. BY SEARCHING THE MESH WORDS "GENE, SILENCING AND LEUKEMIA" IN PUBMED WEBSITE, RELEVANT ENGLISH ARTICLES DEALT WITH HUMAN SUBJECTS AS OF 2000 WERE INCLUDED IN THIS STUDY. GENE INACTIVATION IN LEUKEMIA IS LARGELY MEDIATED BY PROMOTER'S HYPERMETHYLATION OF GENE INVOLVING IN CELLULAR FUNCTIONS SUCH AS CELL CYCLE, APOPTOSIS, AND GENE TRANSCRIPTION. INACTIVATED GENES, SUCH AS ASPP1, TP53, IKZF1 AND P15, MAY CORRELATE WITH POOR PROGNOSIS IN ACUTE LYMPHOID LEUKEMIA (ALL), CHRONIC LYMPHOID LEUKEMIA (CLL), CHRONIC MYELOGENOUS LEUKEMIA (CML) AND ACUTE MYELOID LEUKEMIA (AML), RESPECTIVELY. GENE INACTIVATION MAY PLAY A CONSIDERABLE ROLE IN LEUKEMIA PATHOGENESIS AND PROGNOSIS, WHICH CAN BE CONSIDERED AS COMPLEMENTARY DIAGNOSTIC TESTS TO DIFFERENTIATE DIFFERENT LEUKEMIA TYPES, DETERMINE LEUKEMIA PROGNOSIS, AND ALSO DETECT RESPONSE TO THERAPY. IN GENERAL, THIS REVIEW SHOWED SOME GENES INACTIVATED ONLY IN LEUKEMIA (WITH DIFFERENCES BETWEEN B-ALL, T-ALL, CLL, AML AND CML). THESE DIFFERENCES COULD BE OF INTEREST AS AN ADDITIONAL TOOL TO BETTER CATEGORIZE LEUKEMIA TYPES. FURTHERMORE; BASED ON INACTIVATED GENES, A DIVERSE CLASSIFICATION OF LEUKEMIAS COULD REPRESENT A POWERFUL METHOD TO ADDRESS A TARGETED THERAPY OF THE PATIENTS, IN ORDER TO MINIMIZE SIDE EFFECTS OF CONVENTIONAL THERAPIES AND TO ENHANCE NEW DRUG STRATEGIES. 2017