1 4320 99 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 2 2944 36 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 3 3091 25 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 4 3015 26 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 5 3089 27 GENOMIC AND EPIGENOMIC ALTERATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA IS A COMMON DISEASE IN WESTERN COUNTRIES AND HAS HETEROGENEOUS CLINICAL BEHAVIOR. THE RELEVANCE OF THE GENETIC BASIS OF THE DISEASE HAS COME TO THE FOREFRONT RECENTLY, WITH GENOME-WIDE STUDIES THAT HAVE PROVIDED A COMPREHENSIVE VIEW OF STRUCTURAL VARIANTS, SOMATIC MUTATIONS, AND DIFFERENT LAYERS OF EPIGENETIC CHANGES. THE MUTATIONAL LANDSCAPE IS CHARACTERIZED BY RELATIVELY COMMON COPY NUMBER ALTERATIONS, A FEW MUTATED GENES OCCURRING IN 10-15% OF CASES, AND A LARGE NUMBER OF GENES MUTATED IN A SMALL NUMBER OF CASES. THE EPIGENOMIC PROFILE HAS REVEALED A MARKED REPROGRAMMING OF REGULATORY REGIONS IN TUMOR CELLS COMPARED WITH NORMAL B CELLS. ALL OF THESE ALTERATIONS ARE DIFFERENTIALLY DISTRIBUTED IN CLINICAL AND BIOLOGICAL SUBSETS OF THE DISEASE, INDICATING THAT THEY MAY UNDERLIE THE HETEROGENEOUS EVOLUTION OF THE DISEASE. THESE GLOBAL STUDIES ARE REVEALING THE MOLECULAR COMPLEXITY OF CHRONIC LYMPHOCYTIC LEUKEMIA AND PROVIDE NEW PERSPECTIVES THAT HAVE HELPED TO UNDERSTAND ITS PATHOGENIC MECHANISMS AND IMPROVE THE CLINICAL MANAGEMENT OF PATIENTS. 2020 6 4481 27 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 7 2652 28 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 8 2535 25 EPIGENETICS IN CHRONIC LYMPHOCYTIC LEUKEMIA. ENORMOUS EVIDENCE HAS ACCUMULATED IN THE PAST DECADES THAT ESTABLISHES THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN CANCER AND HAS RESULTED IN SHIFTING THE FOCUS FROM ENTIRELY GENETIC-BASED STUDIES TO INTEGRATED STUDIES INVOLVING BOTH GENETIC AND EPIGENETIC ALTERATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS ONE SUCH EXAMPLE WHERE STUDIES INVOLVING EPIGENETIC ABERRATIONS HAVE ACCELERATED THE SEARCH FOR AFFECTED GENES, WHICH WAS INITIALLY RESTRICTED TO COMMONLY DELETED CHROMOSOMAL REGIONS. MANY NOVEL GENES THAT ARE EPIGENETICALLY SILENCED IN CLL HAVE BEEN IDENTIFIED. ADVANCES IN THE UNDERSTANDING OF POST-TRANSLATIONAL HISTONE MODIFICATIONS AND DNA METHYLATION IN NORMAL AND IN CLL CELLS HAVE PROVEN TO BE EXTREMELY BENEFICIAL IN FINDING POWERFUL DIAGNOSTIC MARKERS, AS WELL AS IN EXPLORING NOVEL THERAPIES. AT PRESENT, THE FIELD OF EPIGENETICS IS AT AN EVOLVING STAGE, BUT THERE IS NO DOUBT THAT FURTHER UNRAVELING OF ITS CAUSE AND EFFECTS IN TRANSFORMED CELLS WILL BRING A NEW REVOLUTION IN CANCER THERAPEUTICS. 2006 9 3768 26 INTEGRATIVE EPIGENOMICS IN CHRONIC LYMPHOCYTIC LEUKAEMIA: BIOLOGICAL INSIGHTS AND CLINICAL APPLICATIONS. CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS NOT ONLY CHARACTERISED BY DRIVER GENETIC ALTERATIONS BUT BY EXTENSIVE EPIGENETIC CHANGES. OVER THE LAST DECADE, EPIGENOMIC STUDIES HAVE DESCRIBED THE DNA METHYLOME, CHROMATIN ACCESSIBILITY, HISTONE MODIFICATIONS AND THE THREE-DIMENSIONAL (3D) GENOME ARCHITECTURE OF CLL. BEYOND ITS REGULATORY ROLE, THE DNA METHYLOME CONTAINS IMPRINTS OF THE CELLULAR ORIGIN AND PROLIFERATIVE HISTORY OF CLL CELLS. THESE TWO ASPECTS ARE STRONG INDEPENDENT PROGNOSTIC FACTORS. INTEGRATIVE ANALYSES OF CHROMATIN MARKS HAVE UNCOVERED NOVEL REGULATORY ELEMENTS AND ALTERED TRANSCRIPTION FACTOR NETWORKS AS NON-GENETIC MEANS MEDIATING GENE DEREGULATION IN CLL. ADDITIONALLY, CLL CELLS DISPLAY A DISEASE-SPECIFIC PATTERN OF 3D GENOME INTERACTIONS. FROM THE TECHNOLOGICAL PERSPECTIVE, WE ARE CURRENTLY WITNESSING A TRANSITION FROM BULK OMICS TO SINGLE-CELL ANALYSES. THIS REVIEW AIMS AT SUMMARISING THE MAJOR FINDINGS FROM THE EPIGENOMICS FIELD AS WELL AS PROVIDING A PROSPECT OF THE PRESENT AND FUTURE OF SINGLE-CELL ANALYSES IN CLL. 2023 10 2074 37 EPIGENETIC DEREGULATION IN CHRONIC LYMPHOCYTIC LEUKEMIA: CLINICAL AND BIOLOGICAL IMPACT. DEREGULATED TRANSCRIPTIONAL CONTROL CAUSED BY ABERRANT DNA METHYLATION AND/OR HISTONE MODIFICATIONS IS A HALLMARK OF CANCER CELLS. IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), THE MOST COMMON ADULT LEUKEMIA, THE EPIGENETIC 'LANDSCAPE' HAS ADDED A NEW LAYER OF COMPLEXITY TO OUR UNDERSTANDING OF THIS CLINICALLY AND BIOLOGICALLY HETEROGENEOUS DISEASE. EARLY STUDIES IDENTIFIED ABERRANT DNA METHYLATION, OFTEN BASED ON SINGLE GENE PROMOTER ANALYSIS WITH BOTH BIOLOGICAL AND CLINICAL IMPACT. SUBSEQUENT GENOME-WIDE PROFILING STUDIES REVEALED DIFFERENTIAL DNA METHYLATION BETWEEN CLLS AND CONTROLS AND IN PROGNOSTICS SUBGROUPS OF THE DISEASE. FROM THESE STUDIES, IT BECAME APPARENT THAT DNA METHYLATION IN REGIONS OUTSIDE OF PROMOTERS, SUCH AS ENHANCERS, IS IMPORTANT FOR THE REGULATION OF CODING GENES AS WELL AS FOR THE REGULATION OF NON-CODING RNAS. ALTHOUGH DNA METHYLATION PROFILES ARE REPORTEDLY STABLE OVER TIME AND IN RELATION TO THERAPY, A HIGHER EPIGENETIC HETEROGENEITY OR 'BURDEN' IS SEEN IN MORE AGGRESSIVE CLL SUBGROUPS, ALBEIT AS NON-RECURRENT 'PASSENGER' EVENTS. MORE RECENTLY, DNA METHYLATION PROFILES IN CLL ANALYZED IN RELATION TO DIFFERENTIATING NORMAL B-CELL POPULATIONS REVEALED THAT THE MAJORITY OF THE CLL EPIGENOME REFLECTS THE EPIGENOMES PRESENT IN THE CELL OF ORIGIN AND THAT ONLY A SMALL FRACTION OF THE EPIGENETIC ALTERATIONS REPRESENTS TRULY CLL-SPECIFIC CHANGES. FURTHERMORE, CLL PATIENTS CAN BE GROUPED INTO AT LEAST THREE CLINICALLY RELEVANT EPIGENETIC SUBGROUPS, POTENTIALLY ORIGINATING FROM DIFFERENT CELLS AT VARIOUS STAGES OF DIFFERENTIATION AND ASSOCIATED WITH DISTINCT OUTCOMES. IN THIS REVIEW, WE SUMMARIZE THE CURRENT UNDERSTANDING OF THE DNA METHYLOME IN CLL, THE ROLE OF HISTONE MODIFYING ENZYMES, HIGHLIGHT INSIGHTS DERIVED FROM ANIMAL MODELS AND ATTEMPTS MADE TO TARGET EPIGENETIC REGULATORS IN CLL ALONG WITH THE FUTURE DIRECTIONS OF THIS RAPIDLY ADVANCING FIELD. 2018 11 6616 30 UNCOVERING THE DNA METHYLOME IN CHRONIC LYMPHOCYTIC LEUKEMIA. OVER THE PAST TWO DECADES, ABERRANT DNA METHYLATION HAS EMERGED AS A KEY PLAYER IN THE PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), AND KNOWLEDGE REGARDING ITS BIOLOGICAL AND CLINICAL CONSEQUENCES IN THIS DISEASE HAS EVOLVED RAPIDLY. SINCE THE INITIAL STUDIES RELATING DNA HYPOMETHYLATION TO GENOMIC INSTABILITY IN CLL, A PLETHORA OF REPORTS HAVE FOLLOWED SHOWING THE IMPACT OF DNA HYPERMETHYLATION IN SILENCING VITAL SINGLE GENE PROMOTERS AND THE REVERSIBLE NATURE OF DNA METHYLATION THROUGH INHIBITOR DRUGS. WITH THE RECOGNITION THAT DNA HYPERMETHYLATION EVENTS COULD POTENTIALLY ACT AS NOVEL PROGNOSTIC AND TREATMENT TARGETS IN CLL, THE SEARCH FOR ABERRANTLY METHYLATED GENES, GENE FAMILIES AND PATHWAYS HAS ENSUED. SUBSEQUENTLY, THE ADVENT OF MICROARRAY AND NEXT-GENERATION SEQUENCING TECHNOLOGIES HAS SUPPORTED THE HUNT FOR SUCH TARGETS, ALLOWING EXPLORATION OF THE METHYLATION LANDSCAPE IN CLL AT AN UNPRECEDENTED SCALE. IN LIGHT OF THESE ANALYSES, WE NOW UNDERSTAND THAT DIFFERENT CLL PROGNOSTIC SUBGROUPS ARE CHARACTERIZED BY DIFFERENTIAL METHYLATION PROFILES; WE RECOGNIZE DNA METHYLATION OF A NUMBER OF SIGNALING PATHWAYS GENES TO BE ALTERED IN CLL, AND ACKNOWLEDGE THE ROLE OF DNA METHYLATION OUTSIDE OF TRADITIONAL CPG ISLAND PROMOTERS AS FUNDAMENTAL PLAYERS IN THE REGULATION OF GENE EXPRESSION. TODAY, THE SIGNIFICANCE AND TIMING OF ALTERED DNA METHYLATION WITHIN THE COMPLEX EPIGENETIC NETWORK OF CONCOMITANT EPIGENETIC MESSENGERS SUCH AS HISTONES AND MIRNAS IS AN INTENSIVE AREA OF RESEARCH. IN CLL, IT APPEARS THAT DNA METHYLATION IS A RATHER STABLE EPIGENETIC MARK OCCURRING RATHER EARLY IN THE DISEASE PATHOGENESIS. HOWEVER, OTHER CONSEQUENCES, SUCH AS HOW AND WHY ABERRANT METHYLATION MARKS OCCUR, ARE LESS EXPLORED. IN THIS REVIEW, WE WILL NOT ONLY PROVIDE A COMPREHENSIVE SUMMARY OF THE CURRENT LITERATURE WITHIN THE EPIGENETICS FIELD OF CLL, BUT ALSO HIGHLIGHT SOME OF THE NOVEL FINDINGS RELATING TO WHEN, WHERE, WHY AND HOW ALTERED DNA METHYLATION MATERIALIZES IN CLL. 2013 12 2992 34 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 13 945 33 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 14 5141 24 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 15 6326 21 THE ROLE OF BCL-2 FAMILY PROTEINS IN CHRONIC LYMPHOCYTIC LEUKAEMIA. BCL-2 FAMILY PROTEINS HAVE LONG BEEN IMPLICATED IN THE PATHOLOGY OF CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). INDEED, A NUMBER OF THESE PROTEINS HAVE BEEN SHOWN TO HAVE PROGNOSTIC IMPORTANCE IN THIS DISEASE. THE PRECISE WAYS IN WHICH THESE PROTEINS IMPACT UPON CLL AND THE WAYS IN WHICH THEY ARE REGULATED REMAIN INCOMPLETELY RESOLVED. HOWEVER, SIGNIFICANT ADVANCES HAVE BEEN RECENTLY MADE IN OUR UNDERSTANDING OF HOW THESE PROTEINS ARE CONTROLLED BY GENETIC, EPIGENETIC AND MICROENVIRONMENTAL CUES. FURTHERMORE, MAJOR PROGRESS HAS BEEN MADE IN TRYING TO TARGET THESE PROTEINS THERAPEUTICALLY. HERE WE REVIEW THE CURRENT KNOWLEDGE ABOUT THIS FAMILY OF APOPTOSIS-REGULATING PROTEINS AND HOW THEY IMPACT UPON DRUG RESISTANCE AND DISEASE PROGRESSION. WE ALSO SUMMARISE EVOLUTION IN THE DEVELOPMENT OF BCL-2 FAMILY INHIBITORS FOR THE TREATMENT OF CLL AND OTHER CANCERS. 2010 16 4473 30 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 17 937 22 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 18 2857 26 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 19 6371 32 THE ROLE OF MICRORNAS IN THE PATHOGENESIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES. MICRORNAS (MIRNAS) COMPRISE A RECENTLY DISCOVERED CLASS OF NON-CODING RNAS WITH REGULATORY FUNCTIONS IN POST-TRANSCRIPTIONAL GENE EXPRESSION CONTROL. MANY MIRNAS ARE LOCATED IN GENOMIC REGIONS THAT ARE FREQUENTLY DELETED IN CANCER, OR ARE SUBJECT TO EPIGENETIC AND TRANSCRIPTIONAL DEREGULATION IN CANCER CELLS. THE MIRNA TRANSCRIPTOME OF CANCER CELLS IS VERY DIFFERENT FROM THAT OF THEIR NORMAL CELL COUNTERPARTS. MIRNAS CAN EXHIBIT ONCOGENIC OR TUMOR SUPPRESSIVE OR EVEN BOTH PROPERTIES DEPENDING ON THE SPECIFIC TARGETS AND CELLULAR CONTEXT. IT IS BECOMING INCREASINGLY CLEAR THAT MIRNAS NOT ONLY SERVE AS USEFUL TUMOR BIOMARKERS WITH IMPLICATIONS FOR DIAGNOSIS, PROGNOSIS AND THE PREDICTION OF TREATMENT RESPONSES, BUT MAY ALSO BE USED FOR TARGETED CANCER TREATMENT AND EVEN AS THERAPEUTICS. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RECENT ADVANCES IN OUR UNDERSTANDING OF THE TUMOR SUPPRESSOR MIRNAS AND ONCOMIRS INVOLVED IN THE PATHOGENESIS OF LEUKEMIAS AND LYMPHOMAS, AND THEIR TARGET TRANSCRIPTS IN CANCER SIGNALING NETWORKS. IN PARTICULAR, WE FOCUS ON THE ROLE OF MIRNAS IN CHRONIC LYMPHOCYTIC AND ACUTE LYMPHOBLASTIC LEUKEMIA AND IN B-CELL LYMPHOMAS. IN THE SECOND PART, WE REVIEW THE VARIOUS ALTERNATIVE STRATEGIES OF TARGETING MIRNAS IN CANCER THERAPY. METHODS OF ONCOMIR ANTAGONIZATION BY ANTAGOMIRS OR LOCKED NUCLEID ACIDS ARE CONTRASTED WITH STRATEGIES THAT HARNESS THE TUMOR SUPPRESSIVE PROPERTIES OF CERTAIN MIRNAS FOR CANCER TREATMENT. PRECLINICAL PROGRESS, ALSO WITH REGARD TO DELIVERY STRATEGIES, POSSIBLE SIDE EFFECTS AND OTHER PHARMACOLOGICAL ASPECTS, IS PRESENTED ALONG WITH RESULTS FROM THE FIRST HUMAN TRIALS ASSESSING THE SAFETY AND EFFICACY OF MIRNA-TARGETING THERAPEUTICS. 2013 20 6854 26 [NEW ADVANCES OF EPIGENETIC STUDY IN TUMORS OF LYMPHATIC SYSTEM---REVIEW]. EPIGENETICS IS AIMED TO STUDY THE HERITABLE CHANGES IN GENE EXPRESSION PATTERNS INDEPENDENT OF ALTERATIONS IN GENOMIC DNA SEQUENCE STRUCTURE, AND THE MECHANISMS OF TRANSLATION FROM GENOTYPE TO PHENOTYPE. IN RECENT YEARS, COMPELLING EVIDENCE GATHERED SUPPORTS A ROLE OF EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF LYMPHATIC SYSTEM TUMORS. FOR EXAMPLE, RECENT DATA FROM MULTIPLE LABORATORIES INDICATE THAT SEVERAL HUNDRED GENES, INVOLVING DOZENS OF CRITICAL MOLECULAR PATHWAYS, ARE EPIGENETICALLY SUPPRESSED IN ACUTE LYMPHOCYTIC LEUKEMIA; A PANEL OF METHYLATION MARKERS CAN BE USED FOR ADDITIONAL RISK STRATIFICATION OF CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS; BASED ON THE EPIGENETIC PROFILES, THE CLASS PREDICTION MODELS IN GRAY ZONE LYMPHOMA CAN BE ESTABLISHED; THE EPIGENETIC SILENCING OF MICRORNAS IN MULTIPLE MYELOMA GENERALLY APPEARS TO HAVE INTACT P53 FUNCTION; EPIGENETIC THERAPIES HAVE BROADER IMPLICATION AND HIGH POTENTIAL FOR THE DEVELOPMENT OF IMMUNOTHERAPEUTIC STRATEGIES AND SO ON. IN THIS REVIEW, THE LATEST ADVANCES OF EPIGENETIC STUDY AND THE PROSPECT OF EPIGENETIC THERAPY FOR TUMORS IN LYMPHATIC SYSTEM ARE SUMMARIZED. 2012