1 1102 106 COMBINED CHEMOSENSITIVITY AND CHROMATIN PROFILING PRIORITIZES DRUG COMBINATIONS IN CLL. THE BRUTON TYROSINE KINASE (BTK) INHIBITOR IBRUTINIB HAS SUBSTANTIALLY IMPROVED THERAPEUTIC OPTIONS FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). ALTHOUGH IBRUTINIB IS NOT CURATIVE, IT HAS A PROFOUND EFFECT ON CLL CELLS AND MAY CREATE NEW PHARMACOLOGICALLY EXPLOITABLE VULNERABILITIES. TO IDENTIFY SUCH VULNERABILITIES, WE DEVELOPED A SYSTEMATIC APPROACH THAT COMBINES EPIGENOME PROFILING (CHARTING THE GENE-REGULATORY BASIS OF CELL STATE) WITH SINGLE-CELL CHEMOSENSITIVITY PROFILING (QUANTIFYING CELL-TYPE-SPECIFIC DRUG RESPONSE) AND BIOINFORMATIC DATA INTEGRATION. BY APPLYING OUR METHOD TO A COHORT OF MATCHED PATIENT SAMPLES COLLECTED BEFORE AND DURING IBRUTINIB THERAPY, WE IDENTIFIED CHARACTERISTIC IBRUTINIB-INDUCED CHANGES THAT PROVIDE A STARTING POINT FOR THE RATIONAL DESIGN OF IBRUTINIB COMBINATION THERAPIES. SPECIFICALLY, WE OBSERVED AND VALIDATED PREFERENTIAL SENSITIVITY TO PROTEASOME, PLK1, AND MTOR INHIBITORS DURING IBRUTINIB TREATMENT. MORE GENERALLY, OUR STUDY ESTABLISHES A BROADLY APPLICABLE METHOD FOR INVESTIGATING TREATMENT-SPECIFIC VULNERABILITIES BY INTEGRATING THE COMPLEMENTARY PERSPECTIVES OF EPIGENETIC CELL STATES AND PHENOTYPIC DRUG RESPONSES IN PRIMARY PATIENT SAMPLES. 2019 2 4487 31 MOLECULARLY TARGETED DRUG COMBINATIONS DEMONSTRATE SELECTIVE EFFECTIVENESS FOR MYELOID- AND LYMPHOID-DERIVED HEMATOLOGIC MALIGNANCIES. TRANSLATING THE GENETIC AND EPIGENETIC HETEROGENEITY UNDERLYING HUMAN CANCERS INTO THERAPEUTIC STRATEGIES IS AN ONGOING CHALLENGE. LARGE-SCALE SEQUENCING EFFORTS HAVE UNCOVERED A SPECTRUM OF MUTATIONS IN MANY HEMATOLOGIC MALIGNANCIES, INCLUDING ACUTE MYELOID LEUKEMIA (AML), SUGGESTING THAT COMBINATIONS OF AGENTS WILL BE REQUIRED TO TREAT THESE DISEASES EFFECTIVELY. COMBINATORIAL APPROACHES WILL ALSO BE CRITICAL FOR COMBATING THE EMERGENCE OF GENETICALLY HETEROGENEOUS SUBCLONES, RESCUE SIGNALS IN THE MICROENVIRONMENT, AND TUMOR-INTRINSIC FEEDBACK PATHWAYS THAT ALL CONTRIBUTE TO DISEASE RELAPSE. TO IDENTIFY NOVEL AND EFFECTIVE DRUG COMBINATIONS, WE PERFORMED EX VIVO SENSITIVITY PROFILING OF 122 PRIMARY PATIENT SAMPLES FROM A VARIETY OF HEMATOLOGIC MALIGNANCIES AGAINST A PANEL OF 48 DRUG COMBINATIONS. THE COMBINATIONS WERE DESIGNED AS DRUG PAIRS THAT TARGET NONOVERLAPPING BIOLOGICAL PATHWAYS AND COMPRISE DRUGS FROM DIFFERENT CLASSES, PREFERABLY WITH FOOD AND DRUG ADMINISTRATION APPROVAL. A COMBINATION RATIO (CR) WAS DERIVED FOR EACH DRUG PAIR, AND CRS WERE EVALUATED WITH RESPECT TO DIAGNOSTIC CATEGORIES AS WELL AS AGAINST GENETIC, CYTOGENETIC, AND CELLULAR PHENOTYPES OF SPECIMENS FROM THE TWO LARGEST DISEASE CATEGORIES: AML AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). NEARLY ALL TESTED COMBINATIONS INVOLVING A BCL2 INHIBITOR SHOWED ADDITIONAL BENEFIT IN PATIENTS WITH MYELOID MALIGNANCIES, WHEREAS SELECT COMBINATIONS INVOLVING PI3K, CSF1R, OR BROMODOMAIN INHIBITORS SHOWED PREFERENTIAL BENEFIT IN LYMPHOID MALIGNANCIES. EXPANDED ANALYSES OF PATIENTS WITH AML AND CLL REVEALED SPECIFIC PATTERNS OF EX VIVO DRUG COMBINATION EFFICACY THAT WERE ASSOCIATED WITH SELECT GENETIC, CYTOGENETIC, AND PHENOTYPIC DISEASE SUBSETS, WARRANTING FURTHER EVALUATION. THESE FINDINGS HIGHLIGHT THE HEURISTIC VALUE OF AN INTEGRATED FUNCTIONAL GENOMIC APPROACH TO THE IDENTIFICATION OF NOVEL TREATMENT STRATEGIES FOR HEMATOLOGIC MALIGNANCIES. 2017 3 2074 32 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 4 2106 37 EPIGENETIC EVOLUTION AND LINEAGE HISTORIES OF CHRONIC LYMPHOCYTIC LEUKAEMIA. GENETIC AND EPIGENETIC INTRA-TUMORAL HETEROGENEITY COOPERATE TO SHAPE THE EVOLUTIONARY COURSE OF CANCER(1). CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS A HIGHLY INFORMATIVE MODEL FOR CANCER EVOLUTION AS IT UNDERGOES SUBSTANTIAL GENETIC DIVERSIFICATION AND EVOLUTION AFTER THERAPY(2,3). THE CLL EPIGENOME IS ALSO AN IMPORTANT DISEASE-DEFINING FEATURE(4,5), AND GROWING POPULATIONS OF CELLS IN CLL DIVERSIFY BY STOCHASTIC CHANGES IN DNA METHYLATION KNOWN AS EPIMUTATIONS(6). HOWEVER, PREVIOUS STUDIES USING BULK SEQUENCING METHODS TO ANALYSE THE PATTERNS OF DNA METHYLATION WERE UNABLE TO DETERMINE WHETHER EPIMUTATIONS AFFECT CLL POPULATIONS HOMOGENEOUSLY. HERE, TO MEASURE THE EPIMUTATION RATE AT SINGLE-CELL RESOLUTION, WE APPLIED MULTIPLEXED SINGLE-CELL REDUCED-REPRESENTATION BISULFITE SEQUENCING TO B CELLS FROM HEALTHY DONORS AND PATIENTS WITH CLL. WE OBSERVED THAT THE COMMON CLONAL ORIGIN OF CLL RESULTS IN A CONSISTENTLY INCREASED EPIMUTATION RATE, WITH LOW VARIABILITY IN THE CELL-TO-CELL EPIMUTATION RATE. BY CONTRAST, VARIABLE EPIMUTATION RATES ACROSS HEALTHY B CELLS REFLECT DIVERSE EVOLUTIONARY AGES ACROSS THE TRAJECTORY OF B CELL DIFFERENTIATION, CONSISTENT WITH EPIMUTATIONS SERVING AS A MOLECULAR CLOCK. HERITABLE EPIMUTATION INFORMATION ALLOWED US TO RECONSTRUCT LINEAGES AT HIGH-RESOLUTION WITH SINGLE-CELL DATA, AND TO APPLY THIS DIRECTLY TO PATIENT SAMPLES. THE CLL LINEAGE TREE SHAPE REVEALED EARLIER BRANCHING AND LONGER BRANCH LENGTHS THAN IN NORMAL B CELLS, REFLECTING RAPID DRIFT AFTER THE INITIAL MALIGNANT TRANSFORMATION AND A GREATER PROLIFERATIVE HISTORY. INTEGRATION OF SINGLE-CELL BISULFITE SEQUENCING ANALYSIS WITH SINGLE-CELL TRANSCRIPTOMES AND GENOTYPING CONFIRMED THAT GENETIC SUBCLONES MAPPED TO DISTINCT CLADES, AS INFERRED SOLELY ON THE BASIS OF EPIMUTATION INFORMATION. FINALLY, TO EXAMINE POTENTIAL LINEAGE BIASES DURING THERAPY, WE PROFILED SERIAL SAMPLES DURING IBRUTINIB-ASSOCIATED LYMPHOCYTOSIS, AND IDENTIFIED CLADES OF CELLS THAT WERE PREFERENTIALLY EXPELLED FROM THE LYMPH NODE AFTER TREATMENT, MARKED BY DISTINCT TRANSCRIPTIONAL PROFILES. THE SINGLE-CELL INTEGRATION OF GENETIC, EPIGENETIC AND TRANSCRIPTIONAL INFORMATION THUS CHARTS THE LINEAGE HISTORY OF CLL AND ITS EVOLUTION WITH THERAPY. 2019 5 3768 23 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 6 5030 28 PERSPECTIVES ON PRECISION MEDICINE IN CHRONIC LYMPHOCYTIC LEUKEMIA: TARGETING RECURRENT MUTATIONS-NOTCH1, SF3B1, MYD88, BIRC3. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS HIGHLY HETEROGENEOUS, WITH EXTREMELY VARIABLE CLINICAL COURSE. THE CLINICAL HETEROGENEITY OF CLL REFLECTS DIFFERENCES IN THE BIOLOGY OF THE DISEASE, INCLUDING CHROMOSOMAL ALTERATIONS, SPECIFIC IMMUNOPHENOTYPIC PATTERNS AND SERUM MARKERS. THE APPLICATION OF NEXT-GENERATION SEQUENCING TECHNIQUES HAS DEMONSTRATED THE HIGH GENETIC AND EPIGENETIC HETEROGENEITY IN CLL. THE NOVEL MUTATIONS COULD BE PHARMACOLOGICALLY TARGETED FOR INDIVIDUALIZED APPROACH IN SOME OF THE CLL PATIENTS. POTENTIAL NEUROGENIC LOCUS NOTCH HOMOLOG PROTEIN 1 (NOTCH1) SIGNALLING TARGETING MECHANISMS IN CLL INCLUDE SECRETASE INHIBITORS AND SPECIFIC ANTIBODIES TO BLOCK NOTCH LIGAND/RECEPTOR INTERACTIONS. IN VITRO STUDIES CHARACTERIZING THE EFFECT OF THE SPLICING INHIBITORS RESULTED IN INCREASED APOPTOSIS OF CLL CELLS REGARDLESS OF SPLICING FACTOR 3B SUBUNIT 1 (SF3B1) STATUS. SEVERAL THERAPEUTIC STRATEGIES HAVE BEEN ALSO PROPOSED TO DIRECTLY OR INDIRECTLY INHIBIT THE TOLL-LIKE RECEPTOR/MYELOID DIFFERENTIATION PRIMARY RESPONSE GENE 88 (TLR/MYD88) PATHWAY. ANOTHER POTENTIAL APPROACH IS TARGETING NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS (NF-KAPPAB) AND INHIBITION OF THIS PROSURVIVAL PATHWAY. NEWLY DISCOVERED MUTATIONS AND THEIR SIGNALLING PATHWAYS PLAY KEY ROLES IN THE COURSE OF THE DISEASE. THIS OPENS NEW OPPORTUNITIES IN THE MANAGEMENT AND TREATMENT OF CLL. 2021 7 3309 27 HIGHER GENE EXPRESSION VARIABILITY IN THE MORE AGGRESSIVE SUBTYPE OF CHRONIC LYMPHOCYTIC LEUKEMIA. BACKGROUND: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PRESENTS TWO SUBTYPES WHICH HAVE DRASTICALLY DIFFERENT CLINICAL OUTCOMES, IGVH MUTATED (M-CLL) AND IGVH UNMUTATED (U-CLL). SO FAR, THESE TWO SUBTYPES ARE NOT ASSOCIATED TO CLEAR DIFFERENCES IN GENE EXPRESSION PROFILES. INTERESTINGLY, RECENT RESULTS HAVE HIGHLIGHTED IMPORTANT ROLES FOR HETEROGENEITY, BOTH AT THE GENETIC AND AT THE EPIGENETIC LEVEL IN CLL PROGRESSION. METHODS: WE ANALYZED GENE EXPRESSION DATA OF TWO LARGE COHORTS OF CLL PATIENTS AND QUANTIFIED EXPRESSION VARIABILITY ACROSS INDIVIDUALS TO INVESTIGATE DIFFERENCES BETWEEN THE TWO SUBTYPES USING DIFFERENT MEASURES AND STATISTICAL TESTS. FUNCTIONAL SIGNIFICANCE WAS EXPLORED BY PATHWAY ENRICHMENT AND NETWORK ANALYSES. FURTHERMORE, WE IMPLEMENTED A RANDOM FOREST APPROACH BASED ON EXPRESSION VARIABILITY TO CLASSIFY PATIENTS INTO DISEASE SUBTYPES. RESULTS: WE FOUND THAT U-CLL, THE MORE AGGRESSIVE TYPE OF THE DISEASE, SHOWS SIGNIFICANTLY INCREASED VARIABILITY OF GENE EXPRESSION ACROSS PATIENTS AND THAT, OVERALL, GENES THAT SHOW HIGHER VARIABILITY IN THE AGGRESSIVE SUBTYPE ARE RELATED TO CELL CYCLE, DEVELOPMENT AND INTER-CELLULAR COMMUNICATION. THESE FUNCTIONS INDICATE A POTENTIAL RELATION BETWEEN GENE EXPRESSION VARIABILITY AND THE FASTER PROGRESSION OF THIS CLL SUBTYPE. FINALLY, A CLASSIFIER BASED ON GENE EXPRESSION VARIABILITY WAS ABLE TO CORRECTLY PREDICT THE DISEASE SUBTYPE OF CLL PATIENTS. CONCLUSIONS: THERE ARE STRONG RELATIONS BETWEEN GENE EXPRESSION VARIABILITY AND DISEASE SUBTYPE LINKING SIGNIFICANTLY INCREASED EXPRESSION VARIABILITY TO PHENOTYPES SUCH AS AGGRESSIVENESS AND RESISTANCE TO THERAPY IN CLL. 2015 8 4254 29 METHYLOME-BASED CELL-OF-ORIGIN MODELING (METHYL-COOM) IDENTIFIES ABERRANT EXPRESSION OF IMMUNE REGULATORY MOLECULES IN CLL. BACKGROUND: IN CANCER, NORMAL EPIGENETIC PATTERNS ARE DISTURBED AND CONTRIBUTE TO GENE EXPRESSION CHANGES, DISEASE ONSET, AND PROGRESSION. THE CANCER EPIGENOME IS COMPOSED OF THE EPIGENETIC PATTERNS PRESENT IN THE TUMOR-INITIATING CELL AT THE TIME OF TRANSFORMATION, AND THE TUMOR-SPECIFIC EPIGENETIC ALTERATIONS THAT ARE ACQUIRED DURING TUMOR INITIATION AND PROGRESSION. THE PRECISE DISSECTION OF THESE TWO COMPONENTS OF THE TUMOR EPIGENOME WILL FACILITATE A BETTER UNDERSTANDING OF THE BIOLOGICAL MECHANISMS UNDERLYING MALIGNANT TRANSFORMATION. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ORIGINATES FROM DIFFERENTIATING B CELLS, WHICH UNDERGO EXTENSIVE EPIGENETIC PROGRAMMING. THIS POSES THE CHALLENGE TO PRECISELY DETERMINE THE EPIGENOMIC GROUND STATE OF THE CELL-OF-ORIGIN IN ORDER TO IDENTIFY CLL-SPECIFIC EPIGENETIC ABERRATIONS. METHODS: WE DEVELOPED A LINEAR REGRESSION MODEL, METHYLOME-BASED CELL-OF-ORIGIN MODELING (METHYL-COOM), TO MAP THE CELL-OF-ORIGIN FOR INDIVIDUAL CLL PATIENTS BASED ON THE CONTINUUM OF EPIGENOMIC CHANGES DURING NORMAL B CELL DIFFERENTIATION. RESULTS: METHYL-COOM ACCURATELY MAPS THE CELL-OF-ORIGIN OF CLL AND IDENTIFIES CLL-SPECIFIC ABERRANT DNA METHYLATION EVENTS THAT ARE NOT CONFOUNDED BY PHYSIOLOGIC EPIGENETIC B CELL PROGRAMMING. FURTHERMORE, METHYL-COOM UNMASKS ABNORMAL ACTION OF TRANSCRIPTION FACTORS, ALTERED SUPER-ENHANCER ACTIVITIES, AND ABERRANT TRANSCRIPT EXPRESSION IN CLL. AMONG THE ABERRANTLY REGULATED TRANSCRIPTS WERE MANY GENES THAT HAVE PREVIOUSLY BEEN IMPLICATED IN T CELL BIOLOGY. FLOW CYTOMETRY ANALYSIS OF THESE MARKERS CONFIRMED THEIR ABERRANT EXPRESSION ON MALIGNANT B CELLS AT THE PROTEIN LEVEL. CONCLUSIONS: METHYL-COOM ANALYSIS OF CLL IDENTIFIED DISEASE-SPECIFIC ABERRANT GENE REGULATION. THE ABERRANTLY EXPRESSED GENES IDENTIFIED IN THIS STUDY MIGHT PLAY A ROLE IN IMMUNE-EVASION IN CLL AND MIGHT SERVE AS NOVEL TARGETS FOR IMMUNOTHERAPY APPROACHES. IN SUMMARY, WE PROPOSE A NOVEL FRAMEWORK FOR IN SILICO MODELING OF REFERENCE DNA METHYLOMES AND FOR THE IDENTIFICATION OF CANCER-SPECIFIC EPIGENETIC CHANGES, A CONCEPT THAT CAN BE BROADLY APPLIED TO OTHER HUMAN MALIGNANCIES. 2020 9 1071 23 CLONAL DYNAMICS IN CHRONIC LYMPHOCYTIC LEUKEMIA. CHRONIC LYMPHOCYTIC LEUKEMIA HAS A HIGHLY VARIABLE DISEASE COURSE ACROSS PATIENTS, THOUGHT TO BE DRIVEN BY THE VAST INTER- AND INTRAPATIENT MOLECULAR HETEROGENEITY DESCRIBED IN SEVERAL LARGE-SCALE DNA-SEQUENCING STUDIES CONDUCTED OVER THE PAST DECADE. ALTHOUGH THE LAST 5 YEARS HAVE SEEN A DRAMATIC SHIFT IN THE THERAPEUTIC LANDSCAPE FOR CHRONIC LYMPHOCYTIC LEUKEMIA, INCLUDING THE REGULATORY APPROVAL OF SEVERAL POTENT TARGETED AGENTS (IE, IDELALISIB, IBRUTINIB, VENETOCLAX), THE VAST MAJORITY OF PATIENTS STILL INEVITABLY EXPERIENCE DISEASE RECURRENCE OR PERSISTENCE. RECENT GENOME-WIDE SEQUENCING APPROACHES HAVE HELPED TO IDENTIFY SUBCLONAL POPULATIONS WITHIN TUMORS THAT DEMONSTRATE A BROAD SPECTRUM OF SOMATIC MUTATIONS, DIVERSE LEVELS OF RESPONSE TO THERAPY, PATTERNS OF REPOPULATION, AND GROWTH KINETICS. UNDERSTANDING THE IMPACT OF GENETIC, EPIGENETIC, AND TRANSCRIPTOMIC FEATURES ON CLONAL GROWTH DYNAMICS AND DRUG RESPONSE WILL BE AN IMPORTANT STEP TOWARD THE SELECTION AND TIMING OF THERAPY. 2019 10 2494 19 EPIGENETICS AND CHRONIC LYMPHOCYTIC LEUKEMIA. THE DNA METHYLATION LEVEL IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IS GENERALLY LOWER THAN HEALTHY INDIVIDUALS. ALTHOUGH DNA METHYLATION IS GLOBALLY DECREASED, REGIONAL HYPERMETHYLATION OF GENE PROMOTERS LEADS TO GENE SILENCING. MANY OF THESE GENES HAVE TUMOR SUPPRESSOR PHENOTYPES. UNLIKE MUTATIONS OR DELETIONS, HYPERMETHYLATION IS POTENTIALLY REVERSIBLE AFTER INHIBITION WITH DNA METHYLATION MODULATORS. MYELODYSPLASTIC SYNDROME HAS BEEN A MODEL DISEASE IN WHICH TREATMENT OF PATIENTS RESULTS IN DEMETHYLATION OF SPECIFIC GENES. THE STORY IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IS SLOWLY UNRAVELING AS EPIGENETIC MODIFICATIONS LIKELY ALSO PLAY AN IMPORTANT ROLE. ONGOING CLINICAL TRIALS CORRELATING CLINICAL RESPONSE TO GENE EXPRESSION AFTER TREATMENT WITH DNA METHYLATION INHIBITORS WILL ULTIMATELY ALLOW US TO BETTER RISK STRATIFY AND PREDICT THE SUBGROUP OF PATIENTS WHO WILL BENEFIT FROM TREATMENT WITH THIS CLASS OF DRUGS. 2006 11 945 22 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 12 3089 24 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 13 4678 30 NEW MOLECULAR MARKERS IN RESISTANT B-CLL. B-CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) IS CHARACTERIZED BY A HIGHLY VARIABLE CLINICAL COURSE WHICH HAS LONG REMAINED A STUMBLING BLOCK FOR CLINICIANS. THIS VARIABILITY APPEARS TO ARISE FROM COMPLEX MOLECULAR ALTERATIONS IDENTIFIED IN MALIGNANT CELLS FROM PATIENT SUBSETS. RECENT STUDIES HAVE FOCUSED IN PARTICULAR ON IDENTIFYING NEW MOLECULAR MARKERS TO HELP PREDICT THE MOST EFFECTIVE AND ADAPTED TREATMENTS. IN ADDITION TO THE MUTATION STATUS OF IMMUNOGLOBULIN VARIABLE HEAVY-CHAIN REGION (IGVH) GENES, WHICH IS A WELL-ESTABLISHED PREDICTIVE FACTOR IN B-CLL, THESE NEW MARKERS INCLUDE DEFECTS OF CELL FACTORS INVOLVED IN THE MAINTENANCE OF GENOME STABILITY, SUCH AS TELOMERE FUNCTION, DNA REPAIR, ATM AND P53. OTHER PREDICTIVE FACTORS, SUCH AS TYROSINE KINASE ZAP-70 AND SOLUBLE FACTORS FOUND IN PATIENT SERA, MAY BE ASSOCIATED WITH B-CELL RECEPTOR SIGNAL TRANSDUCTION. INTERESTINGLY, AN ALTERATION OF THESE FACTORS FITS CLOSELY, THOUGH NOT STRIKINGLY, WITH THE ABSENCE OF SOMATIC MUTATIONS IN IGVH GENES, SUGGESTING THAT THE LATTER MAY BE DUE EITHER TO EPIGENETIC EVENTS LEADING TO AN UNSTABLE GENOME OR TO AN INHERITED DEFECT IN THE IMMUNE RESPONSE OF MALIGNANT B-CELLS. RECENT LESSONS FROM ZAP-70 EXPRESSION/PHOSPHORYLATION SUGGEST THAT SOME OF THESE MARKERS MAY REFLECT THE DEFECTIVE PATHWAYS IN B-CLL CELLS RATHER THAN BEING MARKERS OF CELL MALIGNANCY PER SE. FURTHERMORE, SPECIFIC SUBSETS OF MARKERS ARE FOUND IN PATIENT CELLS RESISTANT TO TREATMENT. CURRENT STUDIES ON GENE EXPRESSION PROFILING AND PROTEOMIC ANALYSES SHOULD SOON LEAD TO A BETTER UNDERSTANDING OF HOW THESE PATHWAYS ARE AFFECTED, ESPECIALLY IN MULTI-DRUG RESISTANT B-CLL. 2006 14 6616 25 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 15 467 23 ARE WE FINALLY GETTING PERSONAL? MOVING TOWARDS A PERSONALIZED APPROACH IN CHRONIC LYMPHOCYTIC LEUKEMIA. WITH ITS HETEROGENEOUS BIOLOGICAL FEATURES AND CLINICAL COURSE, CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), THE MOST FREQUENT ADULT LEUKEMIA IN THE WESTERN WORLD, IS A PARADIGMATIC CONDITION REQUIRING A TAILORED APPROACH AND A PRECISE KNOWLEDGE OF THE BIOLOGY BEHIND EACH INDIVIDUAL PATIENT. THIS PERSONALIZED MANAGEMENT IS BECOMING EVEN MORE CRUCIAL, SINCE, AFTER DECADES OF PRECLINICAL WORK UNRAVELLING THE KEY ROLE OF THE B-CELL RECEPTOR (BCR) SIGNALLING PATHWAYS AND THE ANTI-APOPTOTIC MECHANISMS IN CLL CELL SURVIVAL AND PROLIFERATION, WE HAVE NOW BCR AND BCL2 INHIBITORS AVAILABLE IN CLINICAL PRACTICE. THANKS TO THIS, WE ARE NOW ABLE TO EXPLOIT SPECIFIC BIOMARKERS TO TAILOR OUR TREATMENT STRATEGIES AND IMPROVE LONG-TERM DISEASE CONTROL, PATIENT OUTCOME AND QUALITY OF LIFE. THAT NOTWITHSTANDING, AS THE DISEASE ITSELF REMAINS INCURABLE, NOVEL CHALLENGES AND UNMET CLINICAL NEEDS HAVE RISEN FROM THE INTRODUCTION OF NOVEL TARGETED AGENTS, INCLUDING MECHANISMS OF RESISTANCE AT BOTH GENETIC AND EPIGENETIC LEVELS. IN THIS REVIEW, WE SUMMARIZE THE CURRENTLY ESTABLISHED PREDICTIVE BIOMARKERS (I.E. IGHV MUTATION STATUS AND TP53 GENE DISRUPTION) THAT SHOULD BE APPLIED IN CLINICAL PRACTICE TO INFORM TREATMENT DECISION IN 2021 BUT ALSO DISCUSS THE MOST PROMISING PROGNOSTIC BIOMARKERS (B-CELL RECEPTOR STEREOTYPY, COMPLEX KARYOTYPE, SOMATIC GENE MUTATIONS, MEASURABLE RESIDUAL DISEASE - MRD) THAT MIGHT BECOME KEY TO DEFINE THE MANAGEMENT OF OUR PATIENTS IN A NEAR FUTURE. 2022 16 3015 21 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 2992 24 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 18 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 19 1561 27 DNA METHYLATION OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH DIFFERENTIAL RESPONSE TO CHEMOTHERAPY. ACQUIRED RESISTANCE TO CHEMOTHERAPY IS AN IMPORTANT CLINICAL PROBLEM AND CAN ALSO OCCUR WITHOUT DETECTABLE CYTOGENETIC ABERRATIONS OR GENE MUTATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS MOLECULARLY WELL CHARACTERIZED AND HAS BEEN ELEMENTAL FOR ESTABLISHING CENTRAL PARADIGMS IN ONCOLOGY. THIS PROMPTED US TO CHECK WHETHER SPECIFIC EPIGENETIC CHANGES AT THE LEVEL OF DNA METHYLATION MIGHT UNDERLIE DEVELOPMENT OF TREATMENT RESISTANCE. WE USED ILLUMINA INFINIUM HUMANMETHYLATION450 BEADCHIPS TO OBTAIN DNA METHYLATION PROFILES OF 71 CLL PATIENTS WITH DIFFERENTIAL RESPONSES. THIRTY-SIX PATIENTS WERE CATEGORIZED AS RELAPSED/REFRACTORY AFTER TREATMENT WITH FLUDARABINE OR BENDAMUSTINE AND 21 OF THEM HAD GENETIC ABERRATIONS OF TP53. THE OTHER 35 PATIENTS WERE UNTREATED AT THE TIME OF SAMPLING AND 15 OF THEM HAD GENETIC ABERRATION OF TP53. ALTHOUGH WE COULD NOT CORRELATE CHEMORESISTANCE WITH EPIGENETIC CHANGES, THE PATIENTS WERE COMPREHENSIVELY CHARACTERIZED REGARDING RELEVANT PROGNOSTIC AND MOLECULAR MARKERS (E.G. IGHV MUTATION STATUS, CHROMOSOME ABERRATIONS, TP53 MUTATION STATUS, CLINICAL PARAMETERS), WHICH MAKES OUR DATASET A UNIQUE AND VALUABLE RESOURCE THAT CAN BE USED BY RESEARCHERS TO TEST ALTERNATIVE HYPOTHESES. 2020 20 4446 27 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