1 4426 166 MOLECULAR BASIS OF CHRONIC LYMPHOCYTIC LEUKEMIA DIAGNOSIS AND PROGNOSIS. BACKGROUNDS: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS THE MOST COMMON TYPE OF LEUKEMIA IN ADULTS AND IS CHARACTERIZED BY A CLONAL ACCUMULATION OF MATURE APOPTOSIS-RESISTANT NEOPLASTIC CELLS. IT IS ALSO A HETEROGENEOUS DISEASE WITH A VARIABLE CLINICAL OUTCOME. HERE, WE PRESENT A REVIEW OF CURRENTLY KNOWN (EPI)GENETIC ALTERATIONS THAT ARE RELATED TO THE ETIOLOGY, PROGRESSION AND CHEMO-REFRACTORINESS OF CLL. RELEVANT LITERATURE WAS IDENTIFIED THROUGH A PUBMED SEARCH (1994-2014) OF ENGLISH-LANGUAGE PAPERS USING THE TERMS CLL, SIGNALING PATHWAY, CYTOGENETIC ABNORMALITY, SOMATIC MUTATION, EPIGENETIC ALTERATION AND MICRO-RNA. RESULTS: CLL IS CHARACTERIZED BY THE PRESENCE OF GROSS CHROMOSOMAL ABNORMALITIES, EPIGENETIC ALTERATIONS, MICRO-RNA EXPRESSION ALTERATIONS, IMMUNOGLOBULIN HEAVY CHAIN GENE MUTATIONS AND OTHER GENETIC LESIONS. THE EXPRESSION OF UNMUTATED IMMUNOGLOBULIN HEAVY CHAIN VARIABLE REGION (IGHV) GENES, ZAP-70 AND CD38 PROTEINS, THE OCCURRENCE OF CHROMOSOMAL ABNORMALITIES SUCH AS 17P AND 11Q DELETIONS AND MUTATIONS OF THE NOTCH1, SF3B1 AND BIRC3 GENES HAVE BEEN ASSOCIATED WITH A POOR PROGNOSIS. IN ADDITION, MUTATIONS IN TUMOR SUPPRESSOR GENES, SUCH AS TP53 AND ATM, HAVE BEEN ASSOCIATED WITH REFRACTORINESS TO CONVENTIONAL CHEMOTHERAPEUTIC AGENTS. MICRO-RNA EXPRESSION ALTERATIONS AND ABERRANT METHYLATION PATTERNS IN GENES THAT ARE SPECIFICALLY DEREGULATED IN CLL, INCLUDING THE BCL-2, TCL1 AND ZAP-70 GENES, HAVE ALSO BEEN ENCOUNTERED AND LINKED TO DISTINCT CLINICAL PARAMETERS. CONCLUSIONS: SPECIFIC CHROMOSOMAL ABNORMALITIES AND GENE MUTATIONS MAY SERVE AS DIAGNOSTIC AND PROGNOSTIC INDICATORS FOR DISEASE PROGRESSION AND SURVIVAL. THE IDENTIFICATION OF THESE ANOMALIES BY STATE-OF-THE-ART MOLECULAR (CYTO)GENETIC TECHNIQUES SUCH AS FLUORESCENCE IN SITU HYBRIDIZATION (FISH), COMPARATIVE GENOMIC HYBRIDIZATION (CGH), SINGLE NUCLEOTIDE POLYMORPHISM (SNP) MICROARRAY-BASED GENOMIC PROFILING AND NEXT-GENERATION SEQUENCING (NGS) CAN BE OF PARAMOUNT HELP FOR THE CLINICAL MANAGEMENT OF THESE PATIENTS, INCLUDING OPTIMAL TREATMENT DESIGN. THE EFFICACY OF NOVEL THERAPEUTICS SHOULD TO BE TESTED ACCORDING TO THE PRESENCE OF THESE MOLECULAR LESIONS IN CLL PATIENTS. 2015 2 5687 38 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 3 2944 39 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 4 2689 31 EVOLUTION OF DNA METHYLATION IS LINKED TO GENETIC ABERRATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA. ALTHOUGH CLONAL SELECTION BY GENETIC DRIVER ABERRATIONS IN CANCER IS WELL DOCUMENTED, THE ABILITY OF EPIGENETIC ALTERATIONS TO PROMOTE TUMOR EVOLUTION IS UNDEFINED. WE USED 450K ARRAYS AND NEXT-GENERATION SEQUENCING TO EVALUATE INTRATUMOR HETEROGENEITY AND EVOLUTION OF DNA METHYLATION AND GENETIC ABERRATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). CLL CASES EXHIBIT VAST INTERPATIENT DIFFERENCES IN INTRATUMOR METHYLATION HETEROGENEITY, WITH GENETICALLY CLONAL CASES MAINTAINING LOW METHYLATION HETEROGENEITY AND UP TO 10% OF TOTAL CPGS IN A MONOALLELICALLY METHYLATED STATE. INCREASING METHYLATION HETEROGENEITY CORRELATES WITH ADVANCED GENETIC SUBCLONAL COMPLEXITY. SELECTION OF NOVEL DNA METHYLATION PATTERNS IS OBSERVED ONLY IN CASES THAT UNDERGO GENETIC EVOLUTION, AND INDEPENDENT GENETIC EVOLUTION IS UNCOMMON AND IS RESTRICTED TO LOW-RISK ALTERATIONS. THESE RESULTS REVEAL THAT ALTHOUGH EVOLUTION OF DNA METHYLATION OCCURS IN HIGH-RISK, CLINICALLY PROGRESSIVE CASES, POSITIVE SELECTION OF NOVEL METHYLATION PATTERNS ENTAILS COEVOLUTION OF GENETIC ALTERATION(S) IN CLL. 2014 5 4320 34 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 6 3015 46 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 7 945 51 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 8 5030 43 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 9 1561 41 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 10 349 40 ALTERED DNA METHYLATION PROFILES IN SF3B1 MUTATED CLL PATIENTS. MUTATIONS IN SPLICING FACTOR GENES HAVE A SEVERE IMPACT ON THE SURVIVAL OF CANCER PATIENTS. SPLICING FACTOR 3B SUBUNIT 1 (SF3B1) IS ONE OF THE MOST FREQUENTLY MUTATED GENES IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL); PATIENTS CARRYING THESE MUTATIONS HAVE A POOR PROGNOSIS. SINCE THE SPLICING MACHINERY AND THE EPIGENOME ARE CLOSELY INTERCONNECTED, WE INVESTIGATED WHETHER THESE ALTERATIONS MAY AFFECT THE EPIGENOMES OF CLL PATIENTS. WHILE AN OVERALL HYPOMETHYLATION DURING CLL CARCINOGENESIS HAS BEEN OBSERVED, THE INTERPLAY BETWEEN THE EPIGENETIC STAGE OF THE ORIGINATING B CELLS AND SF3B1 MUTATIONS, AND THE SUBSEQUENT EFFECT OF THE MUTATIONS ON METHYLATION ALTERATIONS IN CLL, HAVE NOT BEEN INVESTIGATED. WE PROFILED THE GENOME-WIDE DNA METHYLATION PATTERNS OF 27 CLL PATIENTS WITH AND WITHOUT SF3B1 MUTATIONS AND IDENTIFIED LOCAL DECREASES IN METHYLATION LEVELS IN SF3B1(MUT) CLL PATIENTS AT 67 GENOMIC REGIONS, MOSTLY IN PROXIMITY TO TELOMERIC REGIONS. THESE DIFFERENTIALLY METHYLATED REGIONS (DMRS) WERE ENRICHED IN GENE BODIES OF CANCER-RELATED SIGNALING GENES, E.G., NOTCH1, HTRA3, AND BCL9L. IN OUR STUDY, SF3B1 MUTATIONS EXCLUSIVELY EMERGED IN TWO OUT OF THREE EPIGENETIC STAGES OF THE ORIGINATING B CELLS. HOWEVER, NOT ALL THE DMRS COULD BE ASSOCIATED WITH THE METHYLATION PROGRAMMING OF B CELLS DURING DEVELOPMENT, SUGGESTING THAT MUTATIONS IN SF3B1 CAUSE ADDITIONAL EPIGENETIC ABERRATIONS DURING CARCINOGENESIS. 2021 11 4678 46 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 12 4446 43 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 13 160 38 ABERRANT PROMOTER HYPOMETHYLATION IN CLL: DOES IT MATTER FOR DISEASE DEVELOPMENT? OVER THE LAST 30 YEARS, STUDIES OF ABERRANT DNA METHYLATION IN HEMATOLOGIC MALIGNANCIES HAVE BEEN DOMINATED BY THE PRIMARY FOCUS OF UNDERSTANDING PROMOTER HYPERMETHYLATION. THESE EFFORTS NOT ONLY RESULTED IN A BETTER UNDERSTANDING OF THE BASIS OF EPIGENETIC SILENCING OF TUMOR SUPPRESSOR GENES BUT ALSO RESULTED IN APPROVAL OF HYPOMETHYLATING AGENTS FOR THE TREATMENT OF SEVERAL MALIGNANCIES, SUCH AS MYELODYSPLASTIC SYNDROME AND ACUTE MYELOID LEUKEMIA. RECENT ADVANCES IN GLOBAL METHYLATION PROFILING COUPLED WITH THE USE OF MOUSE MODELS SUGGEST THAT ABERRANT PROMOTER HYPOMETHYLATION IS ALSO A FREQUENT EVENT IN HEMATOLOGIC MALIGNANCIES, PARTICULARLY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). PROMOTER HYPOMETHYLATION AFFECTS GENE EXPRESSION AND, THEREFORE, MAY PLAY AN IMPORTANT ROLE IN DISEASE PATHOGENESIS. HERE, WE REVIEW RECENT FINDINGS AND DISCUSS THE POTENTIAL INVOLVEMENT OF ABERRANT PROMOTER HYPOMETHYLATION IN CLL. 2016 14 3089 38 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 15 2074 46 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 16 3091 31 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 17 2652 33 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 18 2494 31 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 19 4487 45 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 20 2966 31 GENETIC AND EPIGENETIC PROFILING OF CLL DISEASE PROGRESSION REVEALS LIMITED SOMATIC EVOLUTION AND SUGGESTS A RELATIONSHIP TO MEMORY-CELL DEVELOPMENT. WE EXAMINED GENETIC AND EPIGENETIC CHANGES THAT OCCUR DURING DISEASE PROGRESSION FROM INDOLENT TO AGGRESSIVE FORMS OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) USING SERIAL SAMPLES FROM 27 PATIENTS. ANALYSIS OF DNA MUTATIONS GROUPED THE LEUKEMIA CASES INTO THREE CATEGORIES: EVOLVING (26%), EXPANDING (26%) AND STATIC (47%). THUS, APPROXIMATELY THREE-QUARTERS OF THE CLL CASES HAD LITTLE TO NO GENETIC SUBCLONAL EVOLUTION. HOWEVER, WE IDENTIFIED SIGNIFICANT RECURRENT DNA METHYLATION CHANGES DURING PROGRESSION AT 4752 CPGS ENRICHED FOR REGIONS NEAR POLYCOMB 2 REPRESSIVE COMPLEX (PRC2) TARGETS. PROGRESSION-ASSOCIATED CPGS NEAR THE PRC2 TARGETS UNDERGO METHYLATION CHANGES IN THE SAME DIRECTION DURING DISEASE PROGRESSION AS DURING NORMAL DEVELOPMENT FROM NAIVE TO MEMORY B CELLS. OUR STUDY SHOWS THAT CLL PROGRESSION DOES NOT TYPICALLY OCCUR VIA SUBCLONAL EVOLUTION, BUT THAT CERTAIN CPG SITES UNDERGO RECURRENT METHYLATION CHANGES. OUR RESULTS SUGGEST CLL PROGRESSION MAY INVOLVE DEVELOPMENTAL PROCESSES SHARED IN COMMON WITH THE GENERATION OF NORMAL MEMORY B CELLS. 2015