1 5030 129 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 2 4695 45 NF-KAPPAB ACTIVATION IN CHRONIC LYMPHOCYTIC LEUKEMIA: A POINT OF CONVERGENCE OF EXTERNAL TRIGGERS AND INTRINSIC LESIONS. THE NUCLEAR FACTOR-KAPPAB (NF-KAPPAB) PATHWAY IS CONSTITUTIVELY ACTIVATED IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS, AND HENCE PLAYS A MAJOR ROLE IN DISEASE DEVELOPMENT AND EVOLUTION. IN CONTRAST TO MANY OTHER MATURE B-CELL LYMPHOMAS, ONLY A FEW RECURRENTLY MUTATED GENES INVOLVED IN CANONICAL OR NON-CANONICAL NF-KAPPAB ACTIVATION HAVE BEEN IDENTIFIED IN CLL (I.E. BIRC3, MYD88 AND NFKBIE MUTATIONS) AND OFTEN AT A LOW FREQUENCY. ON THE OTHER HAND, CLL B CELLS SEEM 'ADDICTED' TO THE TUMOR MICROENVIRONMENT FOR THEIR SURVIVAL AND PROLIFERATION, WHICH IS PRIMARILY MEDIATED BY INTERACTION THROUGH A NUMBER OF CELL SURFACE RECEPTORS, E.G. THE B-CELL RECEPTOR (BCR), TOLL-LIKE RECEPTORS AND CD40, THAT IN TURN ACTIVATE DOWNSTREAM NF-KAPPAB. THE IMPORTANCE OF CELL-EXTRINSIC TRIGGERING FOR CLL PATHOPHYSIOLOGY WAS RECENTLY ALSO HIGHLIGHTED BY THE CLINICAL EFFICACY OF NOVEL DRUGS TARGETING MICROENVIRONMENTAL INTERACTIONS THROUGH THE INHIBITION OF BCR SIGNALING. IN OTHER WORDS, CLL CAN BE CONSIDERED A PROTOTYPE DISEASE FOR STUDYING THE INTRICATE INTERPLAY BETWEEN EXTERNAL TRIGGERS AND INTRINSIC ABERRATIONS AND THEIR COMBINED IMPACT ON DISEASE EVOLUTION. IN THIS REVIEW, WE WILL DISCUSS THE CURRENT UNDERSTANDING OF MECHANISMS UNDERLYING NF-KAPPAB DEREGULATION IN CLL, INCLUDING MICRO-ENVIRONMENTAL, GENETIC AND EPIGENETIC EVENTS, AND SUMMARIZE DATA GENERATED IN MURINE MODELS RESEMBLING HUMAN CLL. FINALLY, WE WILL ALSO DISCUSS DIFFERENT STRATEGIES UNDERTAKEN TO INTERVENE WITH THE NF-KAPPAB PATHWAY AND ITS UPSTREAM MEDIATORS. 2016 3 4693 27 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 4 4487 37 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 5 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 6 358 35 ALTERNATIVE SPLICING IN CHRONIC MYELOID LEUKEMIA (CML): A NOVEL THERAPEUTIC TARGET? ALTHOUGH THE IMATINIB BASED THERAPY OF CHRONIC MYELOID LEUKEMIA (CML) REPRESENTS A TRIUMPH OF MEDICINE, NOT ALL PATIENTS WITH CML BENEFIT FROM THIS DRUG DUE TO THE DEVELOPMENT OF RESISTANCE AND INTOLERANCE. THE INTERRUPTION OF IMATINIB TREATMENT IS OFTEN FOLLOWED BY CLINICAL RELAPSE, SUGGESTING A FAILURE IN THE KILLING OF RESIDUAL LEUKAEMIC STEM CELLS. THERE IS NEED TO IDENTIFY ALTERNATIVE SELECTIVE MOLECULAR TARGETS FOR THIS DISEASE AND DEVELOP MORE EFFECTIVE THERAPEUTIC APPROACHES. ALTERNATIVE PRE-MRNA SPLICING (AS) IS AN EPIGENETIC PROCESS THAT GREATLY DIVERSIFIES THE REPERTOIRE OF THE TRANSCRIPTOME. AS ORCHESTRATES INTERACTIONS BETWEEN VARIOUS TYPES OF PROTEINS AND BETWEEN PROTEINS AND NUCLEIC ACIDS. CHANGES CAUSED BY INDIVIDUAL SPLICING EVENTS IN THE CELLS ARE SMALL, HOWEVER, "SPLICING PROGRAMS" TYPICALLY REACT TO THESE INDIVIDUAL CHANGES WITH CONSIDERABLE EFFECTS IN CELL PROLIFERATION, CELL SURVIVAL, AND APOPTOSIS. CURRENT EVIDENCE SUGGESTS A PIVOTAL ROLE OF AS IN LEUKEMIAS, PARTICULARLY IN MYELODISPLASTIC SYNDROME (MDS) AND CHRONIC LYMPHOCYTE LEUKEMIA (CLL). FROM THESE STUDIES AND STUDIES IN OTHER MALIGNANCES, IT IS CLEAR THAT SPLICING ABNORMALITIES PLAY A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION. EVALUATION OF AS EVENTS IN CML CAN BE USED TO IDENTIFY NOVEL DISEASE MARKERS AND DRUGSENSITIVE TARGETS TO OVERCOME THE LIMITS OF THE SMALL MOLECULE INHIBITORS CURRENTLY USED FOR TREATING PATIENTS WITH CML. THE USE OF ABERRANT SPLICE VARIANTS AS DISEASE MARKERS HAS BEEN REPORTED, HOWEVER, LITTLE IS KNOWN ABOUT THE USE OF SPLICING ABNORMALITIES AS DRUG TARGETS IN CML. HEREIN WE DISCUSS POTENTIAL THERAPEUTIC APPROACHES THAT CAN BE USED TO TARGET SPLICING ABNORMALITIES IN CML. 2013 7 4320 32 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 8 945 44 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 9 4426 43 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 10 2652 29 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 11 160 24 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 12 2992 44 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 6326 20 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 14 3089 29 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 2494 29 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 16 5687 33 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 17 3015 41 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 18 3565 41 IMPACT OF GENETIC POLYMORPHISMS AND BIOMARKERS ON THE EFFECTIVENESS AND TOXICITY OF TREATMENT OF CHRONIC MYELOID LEUKEMIA AND ACUTE MYELOID LEUKEMIA. MOST MALIGNANT HEMATOLOGICAL DISEASES ARE GENERALLY A CONSEQUENCE OF ACQUIRED MUTATIONS OR REARRANGEMENTS IN CELL REPLICATION PROCESSES. ACUTE MYELOID LEUKEMIA (AML) IS A CLINICALLY AND MOLECULARLY HETEROGENEOUS DISEASE THAT RESULTS FROM ACQUIRED GENETIC AND EPIGENETIC ALTERATIONS IN HEMATOPOIETIC PROGENITOR CELLS. DESPITE THE ADVANCES MADE IN UNDERSTANDING THE PATHOGENESIS OF THIS DISEASE, THE OVERALL SURVIVAL OF PATIENTS REMAINS VERY LOW DUE TO THE HIGH RELAPSE RATE. PHARMACOGENETICS AND MASSIVE SEQUENCING STUDIES HAVE ALLOWED THE IDENTIFICATION OF NEW RECURRENT MUTATIONS WITH SIGNIFICANT PROGNOSTIC IMPACT IN AML; FURTHERMORE, IT SEEMS LIKELY THAT WHOLE GENOME SEQUENCING WILL SOON BECOME A STANDARD DIAGNOSTIC TEST, WHICH WILL ALLOW THE MOLECULAR DIAGNOSIS OF PATIENTS. THEREFORE, IT IS NECESSARY TO DEVELOP MOLECULAR TARGETS THAT OPEN NEW THERAPEUTIC PERSPECTIVES AND ALLOW INDIVIDUALIZED TREATMENT OF PATIENTS WITH THIS AGGRESSIVE DISEASE. CHRONIC MYELOID LEUKEMIA (CML) IS THE FIRST NEOPLASTIC DISEASE FOR WHICH A CHARACTERISTIC GENETIC ALTERATION WAS DESCRIBED. IT HAS, BY DEFINITION, A GENETIC MARKER, THE BCR::ABL1 REARRANGEMENT, AS A CONSEQUENCE OF THE T9;22(Q34;Q11) TRANSLOCATION. ITS STUDY IS ESSENTIAL FOR THE DIAGNOSIS OF THIS ENTITY AND ALSO FOR MONITORING THE RESPONSE TO TREATMENT. DRUGS KNOWN AS TYROSINE KINASE INHIBITORS (TKIS) THAT TARGET THE BCR::ABL1 PROTEIN (ORAL TARGETED THERAPY) ARE THE CONVENTIONAL TREATMENT OF CML, REPRESENTING A CHANGE OF PARADIGM IN THE MANAGEMENT OF ONCOHEMATOLOGICAL PATIENTS. 2022 19 4678 39 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 20 2781 34 EZH2 IN MYELOID MALIGNANCIES. OUR UNDERSTANDING OF THE SIGNIFICANCE OF EPIGENETIC DYSREGULATION IN THE PATHOGENESIS OF MYELOID MALIGNANCIES HAS GREATLY ADVANCED IN THE PAST DECADE. ENHANCER OF ZESTE HOMOLOG 2 (EZH2) IS THE CATALYTIC CORE COMPONENT OF THE POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), WHICH IS RESPONSIBLE FOR GENE SILENCING THROUGH TRIMETHYLATION OF H3K27. EZH2 DYSREGULATION IS HIGHLY TUMORIGENIC AND HAS BEEN OBSERVED IN VARIOUS CANCERS, WITH EZH2 ACTING AS AN ONCOGENE OR A TUMOR-SUPPRESSOR DEPENDING ON CELLULAR CONTEXT. WHILE LOSS-OF-FUNCTION MUTATIONS OF EZH2 FREQUENTLY AFFECT PATIENTS WITH MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS, MYELODYSPLASTIC SYNDROME AND MYELOFIBROSIS, CASES OF CHRONIC MYELOID LEUKEMIA (CML) SEEM TO BE LARGELY CHARACTERIZED BY EZH2 OVEREXPRESSION. A VARIETY OF OTHER FACTORS FREQUENTLY ABERRANT IN MYELOID LEUKEMIA CAN AFFECT PRC2 FUNCTION AND DISEASE PATHOGENESIS, INCLUDING ADDITIONAL SEX COMBS LIKE 1 (ASXL1) AND SPLICING GENE MUTATIONS. AS THE GENETIC BACKGROUND OF MYELOID MALIGNANCIES IS LARGELY HETEROGENEOUS, IT IS NOT SURPRISING THAT EZH2 MUTATIONS ACT IN CONJUNCTION WITH OTHER ABERRATIONS. SINCE EZH2 MUTATIONS ARE CONSIDERED TO BE EARLY EVENTS IN DISEASE PATHOGENESIS, THEY ARE OF THERAPEUTIC INTEREST TO RESEARCHERS, THOUGH TARGETING OF EZH2 LOSS-OF-FUNCTION DOES PRESENT UNIQUE CHALLENGES. PRELIMINARY RESEARCH INDICATES THAT COMBINED TYROSINE KINASE INHIBITOR (TKI) AND EZH2 INHIBITOR THERAPY MAY PROVIDE A STRATEGY TO ELIMINATE THE RESIDUAL DISEASE BURDEN IN CML TO ALLOW PATIENTS TO REMAIN IN TREATMENT-FREE REMISSION. 2020