1 439 136 ANTILEUKEMIC ACTIVITY OF VALPROIC ACID IN CHRONIC LYMPHOCYTIC LEUKEMIA B CELLS DEFINED BY MICROARRAY ANALYSIS. EPIGENETIC CODE MODIFICATIONS BY HISTONE DEACETYLASE INHIBITORS HAVE RECENTLY BEEN PROPOSED AS POTENTIAL NEW THERAPIES FOR HEMATOLOGICAL MALIGNANCIES. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) REMAINS INCURABLE DESPITE THE INTRODUCTION OF NEW TREATMENTS. CLL B CELLS ARE CHARACTERIZED BY AN APOPTOSIS DEFECT RATHER THAN EXCESSIVE PROLIFERATION, BUT PROLIFERATION CENTERS HAVE BEEN FOUND IN ORGANS SUCH AS THE BONE MARROW AND LYMPH NODES. IN THIS STUDY, WE ANALYZED GENE EXPRESSION MODIFICATIONS IN CLL B CELLS AFTER TREATMENT WITH VALPROIC ACID (VPA), A WELL-TOLERATED ANTI-EPILEPTIC DRUG WITH HDAC INHIBITORY ACTIVITY. CLL B CELLS OBTAINED FROM 14 PATIENTS WERE TREATED IN VITRO WITH A CONCENTRATION OF 1 MM VPA FOR 4 H. VPA EFFECTS ON GENE EXPRESSION WERE THEREAFTER STUDIED USING AFFYMETRIX TECHNOLOGY, AND SOME IDENTIFIED GENES WERE VALIDATED BY REAL-TIME PCR AND WESTERN BLOT. WE OBSERVED THAT VPA INDUCED APOPTOSIS BY DOWNREGULATING SEVERAL ANTI-APOPTOTIC GENES AND BY UPREGULATING PRO-APOPTOTIC GENES. FURTHERMORE, VPA SIGNIFICANTLY INCREASED CHEMOSENSITIVITY TO FLUDARABINE, FLAVOPIRIDOL, BORTEZOMIB, THALIDOMIDE AND LENALIDOMIDE. VPA INHIBITED THE PROLIFERATION OF CPG/IL2-STIMULATED CLL B CELLS AND MODULATED MANY CELL CYCLE MESSENGER RNAS. IN CONCLUSION, EXPOSURE OF CLL B CELLS TO VPA INDUCED APOPTOSIS, POTENTIATED CHEMOTHERAPEUTIC AGENT EFFECTS AND INHIBITED PROLIFERATION. THESE DATA STRONGLY SUGGEST THE USE OF VPA IN CLL TREATMENT, PARTICULARLY IN COMBINATION WITH ANTILEUKEMIA AGENTS. 2009 2 557 31 B-CELL ANTIGEN RECEPTOR SIGNALING IN CHRONIC LYMPHOCYTIC LEUKEMIA: THERAPEUTIC TARGETS AND TRANSLATIONAL OPPORTUNITIES. B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY CLONALLY EXPANDED AND MOLECULARLY HETEROGENEOUS POPULATIONS OF B LYMPHOCYTES WITH IMPAIRED APOPTOTIC MECHANISMS. THIS OCCURS AS A RESULT OF MULTIPLE GENETIC AND EPIGENETIC ABNORMALITIES, INCLUDING CHROMOSOMAL ABERRATIONS AND ENHANCER REGION HYPOMETHYLATION, OFTEN IMPINGING ON INTRACELLULAR SIGNALING PATHWAYS THAT ARE ESSENTIAL TO NORMAL B-CELL ACTIVATION, PROLIFERATION, AND SURVIVAL. THE B-CELL ANTIGEN RECEPTOR (BCR) SIGNALING IS ONE SUCH PATHWAY USURPED BY MALIGNANT B CELLS, AS EXEMPLIFIED BY THE EARLY PHASE CLINICAL SUCCESS ACHIEVED BY SMALL-MOLECULE AGENTS TARGETING KEY PLAYERS INVOLVED IN THE PATHWAY. SUCH NEW TARGETED AGENTS, INCLUDING THOSE THAT INHIBIT THE FUNCTION OF SPLEEN TYROSINE KINASE (SYK), BRUTON'S TYROSINE KINASE (BTK), PHOSPHATIDYLINOSITOL 3-KINASES (PI3K), AND B-CELL LYMPHOMA 2 (BCL-2), ALONG WITH THE CURRENT STANDARD THERAPY COMPRISING CHEMO-IMMUNOTHERAPIES WITH OR WITHOUT B-CELL DEPLETING BIOLOGIC AGENT RITUXIMAB (ANTI-CD20 MONOCLONAL ANTIBODY), SHOULD EXPAND THE ARMAMENTARIUM FOR CLL THERAPY. WE REVIEW THE THERAPEUTIC AGENTS CURRENTLY IN CLINICAL DEVELOPMENT WHICH TARGET DIFFERENT EFFECTORS OF THE MALIGNANT BCR SIGNALING, AND DISCUSS THEIR OVERLAPPING AND DISCRIMINATING TRANSLATIONAL OPPORTUNITIES IN THE CONTEXT OF CLL TREATMENT. 2013 3 5512 23 RICHTER SYNDROME IN CHRONIC LYMPHOCYTIC LEUKEMIA: UPDATES ON BIOLOGY, CLINICAL FEATURES AND THERAPY. RICHTER SYNDROME (RS) OR RICHTER TRANSFORMATION IS THE DEVELOPMENT OF SECONDARY AGGRESSIVE LYMPHOMA IN THE SETTING OF UNDERLYING CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA (CLL/SLL). MOST FREQUENTLY CLL TRANSFORMS INTO DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) (90%) AND RARELY (10%) INTO HODGKIN LYMPHOMA, TERMED HODGKIN VARIANT OF RICHTER SYNDROME (HVRS). RS IS GENERALLY CHARACTERIZED BY AN AGGRESSIVE CLINICAL COURSE AND POOR PROGNOSIS. IN RECENT YEARS, MAJOR ADVANCES HAVE BEEN MADE IN UNDERSTANDING GENETIC EVENTS WHICH RELATE TO THE PROGRESSION OF CLL OR TRANSFORMATION INTO RS. BETTER UNDERSTANDING OF THE MOLECULAR PATHWAYS HAS REVEALED THAT RS IS NOT A SINGLE HOMOGENEOUS ENTITY. THE MAJORITY OF CASES ARE CLONALLY RELATED TO THE ORIGINAL CLL CLONE, WHILE A MINORITY DEVELOP FROM AN UNRELATED CLONE. THIS REVIEW SUMMARIZES NEW DATA RELATING TO THE MOLECULAR BIOLOGY AND THE GENETIC/EPIGENETIC CHANGES OCCURRING DURING RICHTER TRANSFORMATION, AND ALSO CONSIDERS THE CLINICAL FEATURES AND THERAPY FOR BOTH DLBCL-RS AND HODGKIN VARIANT-RS. 2015 4 5513 30 RICHTER SYNDROME: NOVEL INSIGHTS INTO THE BIOLOGY OF TRANSFORMATION. ALTHOUGH THE GENETIC LANDSCAPE OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) HAS BEEN BROADLY PROFILED BY LARGE-SCALE SEQUENCING STUDIES PERFORMED OVER THE PAST DECADE, THE MOLECULAR BASIS OF THE TRANSFORMATION OF CLL INTO AGGRESSIVE LYMPHOMA, OR RICHTER SYNDROME (RS), HAS REMAINED INCOMPLETELY CHARACTERIZED. RECENT ADVANCES IN COMPUTATIONAL METHODS OF CLONAL DECONVOLUTION, AS WELL AS EXTENSIVE SAMPLE COLLECTION EFFORTS IN THIS RAPIDLY PROGRESSIVE MALIGNANCY, HAVE NOW ENABLED COMPREHENSIVE ANALYSIS OF PAIRED CLL AND RS SAMPLES AND HAVE LED TO MULTIPLE NEW STUDIES INVESTIGATING THE GENETIC, TRANSCRIPTOMIC, AND EPIGENETIC ORIGINS OF RS. IN PARALLEL, NEW GENETICALLY ENGINEERED AND XENOGRAFT MOUSE MODELS HAVE PROVIDED THE OPPORTUNITY FOR GLEANING FRESH BIOLOGICAL AND MECHANISTIC INSIGHTS INTO RS DEVELOPMENT AND STEPWISE EVOLUTION FROM ANTECEDENT CLL. ALTOGETHER, THESE STUDIES HAVE DEFINED RS DRIVER LESIONS AND CLL RISK LESIONS AND IDENTIFIED PATHWAYS DYSREGULATED IN TRANSFORMATION. MOREOVER, UNIQUE MOLECULAR SUBTYPES OF RS HAVE BEEN REVEALED, INCLUDING A DISEASE MARKED BY PROFOUND GENOMIC INSTABILITY WITH CHROMOTHRIPSIS/CHROMOPLEXY AND WHOLE GENOME DUPLICATION. NOVEL PROFILING APPROACHES, INCLUDING SINGLE-CELL DNA AND TRANSCRIPTOME SEQUENCING OF RS BIOPSY SPECIMENS AND CELL-FREE DNA PROFILING OF PATIENT PLASMA, DEMONSTRATE PROMISE FOR THE TIMELY IDENTIFICATION OF RS CLONES AND MAY TRANSLATE TO NONINVASIVE IDENTIFICATION AND EARLY DIAGNOSIS OF RS. THIS REVIEW SUMMARIZES THE RECENT SCIENTIFIC ADVANCES IN RS AND SUPPORTS THE INTEGRATED STUDY OF HUMAN GENOMICS WITH MOUSE MODELING TO PROVIDE AN ADVANCED UNDERSTANDING OF THE BIOLOGICAL UNDERPINNINGS OF TRANSFORMATION. THESE RECENT STUDIES HAVE MAJOR IMPLICATIONS FOR MUCH-NEEDED NOVEL THERAPEUTIC STRATEGIES FOR THIS STILL LARGELY INCURABLE MALIGNANCY. 2023 5 467 33 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 6 5462 23 RESEARCH PROGRESS ON EPIGENETICS OF SMALL B-CELL LYMPHOMA. SMALL B-CELL LYMPHOMA IS THE CLASSIFICATION OF B-CELL CHRONIC LYMPHOPROLIFERATIVE DISORDERS THAT INCLUDE CHRONIC LYMPHOCYTIC LEUKAEMIA/SMALL LYMPHOCYTIC LYMPHOMA, FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA. THE CLINICAL PRESENTATION IS SOMEWHAT HETEROGENEOUS, AND ITS OCCURRENCE AND DEVELOPMENT MECHANISMS ARE NOT YET PRECISE AND MAY INVOLVE EPIGENETIC CHANGES. EPIGENETIC ALTERATIONS MAINLY INCLUDE DNA METHYLATION, HISTONE MODIFICATION, AND NON-CODING RNA, WHICH ARE ESSENTIAL FOR GENETIC DETECTION, EARLY DIAGNOSIS, AND ASSESSMENT OF TREATMENT RESISTANCE IN SMALL B-CELL LYMPHOMA. AS CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA HAS ALREADY BEEN REPORTED IN THE LITERATURE, THIS ARTICLE FOCUSES ON SMALL B-CELL LYMPHOMAS SUCH AS FOLLICULAR LYMPHOMA, MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA, AND WALDENSTROM MACROGLOBULINEMIA. IT DISCUSSES RECENT DEVELOPMENTS IN EPIGENETIC RESEARCH TO DIAGNOSE AND TREAT THIS GROUP OF LYMPHOMAS. THIS REVIEW PROVIDES NEW IDEAS FOR THE TREATMENT AND PROGNOSIS ASSESSMENT OF SMALL B-CELL LYMPHOMA BY EXPLORING THE CONNECTION BETWEEN SMALL B-CELL LYMPHOMA AND EPIGENETICS. 2022 7 1102 33 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 8 5141 27 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 9 5691 42 SILENCING OF HDAC6 AS A THERAPEUTIC TARGET IN CHRONIC LYMPHOCYTIC LEUKEMIA. ALTHOUGH THE TREATMENT PARADIGM FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS RAPIDLY CHANGING, THE DISEASE REMAINS INCURABLE, EXCEPT WITH ALLOGENEIC BONE MARROW TRANSPLANTATION, AND RESISTANCE, RELAPSED DISEASE, AND PARTIAL RESPONSES PERSIST AS SIGNIFICANT CHALLENGES. RECENT STUDIES HAVE UNCOVERED ROLES FOR EPIGENETIC MODIFICATION IN THE REGULATION OF MECHANISMS CONTRIBUTING TO MALIGNANT PROGRESSION OF CLL B CELLS. HOWEVER, THE EXTENT TO WHICH EPIGENETIC MODIFIERS CAN BE TARGETED FOR THERAPEUTIC BENEFIT IN CLL PATIENTS REMAINS POORLY EXPLORED. WE REPORT FOR THE FIRST TIME THAT EXPRESSION OF EPIGENETIC MODIFIER HISTONE DEACETYLASE 6 (HDAC6) IS UPREGULATED IN CLL PATIENT SAMPLES, CELL LINES, AND EUTCL1 TRANSGENIC MOUSE MODELS COMPARED WITH HDAC6 IN NORMAL CONTROLS. GENETIC SILENCING OF HDAC6 CONFERRED SURVIVAL BENEFIT IN EUTCL1 MICE. ADMINISTRATION OF ISOFORM-SPECIFIC HDAC6 INHIBITOR ACY738 IN THE EUTCL1 AGING AND ADOPTIVE TRANSFER MODELS DETERRED PROLIFERATION OF CLL B CELLS, DELAYED DISEASE ONSET VIA DISRUPTION OF B-CELL RECEPTOR SIGNALING, AND SENSITIZED CLL B CELLS TO APOPTOSIS. FURTHERMORE, COADMINISTRATION OF ACY738 AND IBRUTINIB DISPLAYED SYNERGISTIC CELL KILL AGAINST CLL CELL LINES AND IMPROVED OVERALL SURVIVAL COMPARED WITH EITHER SINGLE AGENT IN VIVO. THESE RESULTS DEMONSTRATE FOR THE FIRST TIME THE THERAPEUTIC EFFICACY OF SELECTIVE HDAC6 INHIBITION IN PRECLINICAL CLL MODELS AND SUGGEST A RATIONALE FOR THE CLINICAL DEVELOPMENT OF HDAC6 INHIBITORS FOR CLL TREATMENT, EITHER ALONE OR IN COMBINATION WITH BRUTON TYROSINE KINASE INHIBITION. 2018 10 1333 38 DEREGULATION AND EPIGENETIC MODIFICATION OF BCL2-FAMILY GENES CAUSE RESISTANCE TO VENETOCLAX IN HEMATOLOGIC MALIGNANCIES. THE BCL2 INHIBITOR VENETOCLAX HAS BEEN APPROVED TO TREAT DIFFERENT HEMATOLOGICAL MALIGNANCIES. BECAUSE THERE IS NO COMMON GENETIC ALTERATION CAUSING RESISTANCE TO VENETOCLAX IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND B-CELL LYMPHOMA, WE ASKED IF EPIGENETIC EVENTS MIGHT BE INVOLVED IN VENETOCLAX RESISTANCE. THEREFORE, WE EMPLOYED WHOLE-EXOME SEQUENCING, METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING, AND GENOME-WIDE CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS (CRISPR)/CRISPR-ASSOCIATED PROTEIN 9 SCREENING TO INVESTIGATE VENETOCLAX RESISTANCE IN AGGRESSIVE LYMPHOMA AND HIGH-RISK CLL PATIENTS. WE IDENTIFIED A REGULATORY CPG ISLAND WITHIN THE PUMA PROMOTER THAT IS METHYLATED UPON VENETOCLAX TREATMENT, MEDIATING PUMA DOWNREGULATION ON TRANSCRIPT AND PROTEIN LEVEL. PUMA EXPRESSION AND SENSITIVITY TOWARD VENETOCLAX CAN BE RESTORED BY INHIBITION OF METHYLTRANSFERASES. WE CAN DEMONSTRATE THAT LOSS OF PUMA RESULTS IN METABOLIC REPROGRAMMING WITH HIGHER OXIDATIVE PHOSPHORYLATION AND ADENOSINE TRIPHOSPHATE PRODUCTION, RESEMBLING THE METABOLIC PHENOTYPE THAT IS SEEN UPON VENETOCLAX RESISTANCE. ALTHOUGH PUMA LOSS IS SPECIFIC FOR ACQUIRED VENETOCLAX RESISTANCE BUT NOT FOR ACQUIRED MCL1 RESISTANCE AND IS NOT SEEN IN CLL PATIENTS AFTER CHEMOTHERAPY-RESISTANCE, BAX IS ESSENTIAL FOR SENSITIVITY TOWARD BOTH VENETOCLAX AND MCL1 INHIBITION. AS WE FOUND LOSS OF BAX IN RICHTER'S SYNDROME PATIENTS AFTER VENETOCLAX FAILURE, WE DEFINED BAX-MEDIATED APOPTOSIS TO BE CRITICAL FOR DRUG RESISTANCE BUT NOT FOR DISEASE PROGRESSION OF CLL INTO AGGRESSIVE DIFFUSE LARGE B-CELL LYMPHOMA IN VIVO. A COMPOUND SCREEN REVEALED TRAIL-MEDIATED APOPTOSIS AS A TARGET TO OVERCOME BAX DEFICIENCY. FURTHERMORE, ANTIBODY OR CAR T CELLS ELIMINATED VENETOCLAX RESISTANT LYMPHOMA CELLS, PAVING A CLINICALLY APPLICABLE WAY TO OVERCOME VENETOCLAX RESISTANCE. 2022 11 5030 33 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 12 941 35 CHRONIC LYMPHOCYTIC LEUKEMIA B-CELL NORMAL CELLULAR COUNTERPART: CLUES FROM A FUNCTIONAL PERSPECTIVE. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY THE CLONAL EXPANSION OF SMALL MATURE-LOOKING CD19+ CD23+ CD5+ B-CELLS THAT ACCUMULATE IN THE BLOOD, BONE MARROW, AND LYMPHOID ORGANS. TO DATE, NO CONSENSUS HAS BEEN REACHED CONCERNING THE NORMAL CELLULAR COUNTERPART OF CLL B-CELLS AND SEVERAL B-CELL TYPES HAVE BEEN PROPOSED. CLL B-CELLS HAVE REMARKABLE PHENOTYPIC AND GENE EXPRESSION PROFILE HOMOGENEITY. IN RECENT YEARS, THE MOLECULAR AND CELLULAR BIOLOGY OF CLL HAS BEEN ENRICHED BY SEMINAL INSIGHTS THAT ARE LEADING TO A BETTER UNDERSTANDING OF THE NATURAL HISTORY OF THE DISEASE. IMMUNOPHENOTYPIC AND MOLECULAR APPROACHES (INCLUDING IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE GENE MUTATIONAL STATUS, TRANSCRIPTIONAL AND EPIGENETIC PROFILING) COMPARING THE NORMAL B-CELL SUBSET AND CLL B-CELLS PROVIDE SOME NEW INSIGHTS INTO THE NORMAL CELLULAR COUNTERPART. FUNCTIONAL CHARACTERISTICS (INCLUDING ACTIVATION REQUIREMENTS AND PROPENSITY FOR PLASMA CELL DIFFERENTIATION) OF CLL B-CELLS HAVE NOW BEEN INVESTIGATED FOR 50 YEARS. B-CELL SUBSETS DIFFER SUBSTANTIALLY IN TERMS OF THEIR FUNCTIONAL FEATURES. ANALYSIS OF SHARED FUNCTIONAL CHARACTERISTICS MAY REVEAL SIMILARITIES BETWEEN NORMAL B-CELL SUBSETS AND CLL B-CELLS, ALLOWING SPECULATIVE ASSIGNMENT OF A NORMAL CELLULAR COUNTERPART FOR CLL B-CELLS. IN THIS REVIEW, WE SUMMARIZE CURRENT DATA REGARDING PERIPHERAL B-CELL DIFFERENTIATION AND HUMAN B-CELL SUBSETS AND SUGGEST POSSIBILITIES FOR A NORMAL CELLULAR COUNTERPART BASED ON THE FUNCTIONAL CHARACTERISTICS OF CLL B-CELLS. HOWEVER, A DEFINITIVE NORMAL CELLULAR COUNTERPART CANNOT BE ATTRIBUTED ON THE BASIS OF THE AVAILABLE DATA. WE DISCUSS THE FUNCTIONAL CHARACTERISTICS REQUIRED FOR A CELL TO BE LOGICALLY CONSIDERED TO BE THE NORMAL COUNTERPART OF CLL B-CELLS. 2018 13 6857 35 [NOVEL CONVENTIONAL THERAPIES IN ONCO-HEMATHOLOGY]. CYTOGENETIC, MOLECULAR AND PHENOTYPING FEATURES OF MALIGNANT HEMATOLOGIC DISEASES SUCCEEDED IN IMPROVING THEIR MANAGEMENT BY A MORE ACCURATE STRATIFICATION OF PATIENTS ACCORDING TO SEVERAL GROUPS OF RISK AND BY PROVIDING A RATIONAL FOR TARGETED THERAPY. THREE MAJOR TYPES OF TREATMENT (EXCLUDING CELLULAR THERAPY) ARE CURRENTLY AVAILABLE IN ONCO-HEMATOLOGY: CONVENTIONAL CHEMOTHERAPY, SMALL MOLECULES FOR TARGETED THERAPY AND MONOCLONAL ANTIBODIES. CONVENTIONAL CHEMOTHERAPY WITH OPTIMIZATION OF DOSES AND MULTIDRUG-BASED REGIMENS ALLOWED TO SUBSTANTIALLY IMPROVE SURVIVAL OF PATIENTS AND KEEPS A PLACE OF CHOICE IN TREATMENT OF THESE DISEASES. TARGETED TREATMENTS CAME FROM THE CYTOGENETIC AND MOLECULAR CHARACTERIZATION OF HEMOPATHIES. THUS, THE KINASE BCR-ABL, AS A RESULT OF THE TRANSLOCATION T(9;22)(Q34;Q11), HAS BEEN SUCCESSFULLY TARGETED BY TYROSINE KINASE INHIBITORS (TKI) IN CHRONIC MYELOID LEUKEMIA AND PH+ ACUTE LYMPHOBLASTIC LEUKEMIA. MOLECULAR ABNORMALITIES LIKE INTERNAL-TANDEM DUPLICATION/POINT ACTIVATING MUTATIONS IN FLT3 IN SOME ACUTE MYELOBLASTIC LEUKEMIA OR EPIGENETIC DYSREGULATIONS IN SOME BLOOD MALIGNANCIES CAN ALSO BE TARGETED BY SMALL MOLECULES. HEMATOPOIETIC MALIGNANT CELLS ARE PHENOTYPICALLY CHARACTERIZED BY EXPRESSION OF CLUSTER OF DIFFERENTIATION (CD) ON THEIR SURFACE. THESE CD ARE DETECTED BY FLOW CYTOMETRY USING SPECIFIC ANTIBODIES. MONOCLONAL ANTIBODIES TARGETING DIFFERENT CD HAVE BEEN DEVELOPED FOR TREATMENT. RITUXIMAB, AN ANTI-CD20 ANTIBODY, WAS THE FIRST MONOCLONAL ANTIBODY SUCCESSFULLY DEVELOPED FOR TREATMENT OF MALIGNANT HEMATOLOGIC DISEASES. SINCE RITUXIMAB, MANY OTHER MONOCLONAL ANTIBODIES ARE BEING DEVELOPED. TRENDS IN MALIGNANT HEMATOLOGIC DISEASES PRESENTED HERE WILL INCLUDE TREATMENTS, WHICH HAVE AT LEAST ENTERED PHASE I/II CLINICAL TRIALS IN ADULT OR CHILDHOOD LEUKEMIA. THEY INCLUDE SOME NOVEL DRUGS OF CONVENTIONAL CHEMOTHERAPY LIKE SECOND-GENERATION NUCLEOSIDE ANALOGUES. WE WILL GIVE AN OVERVIEW OF THE SMALL MOLECULES TARGETING THE DIFFERENT CELLULAR PATHWAYS AND WE WILL HIGHLIGHT THOSE APPEARING AS THE MOST PROMISING LIKE NOVEL TKIS. THE LARGE FIELD OF MONOCLONAL ANTIBODIES WILL BE ALSO APPROACHED FOCUSING ON ANTIBODIES DEVELOPED IN LEUKEMIAS. 2011 14 5477 37 RESTORING THE FUNCTIONAL IMMUNOGENICITY OF CHRONIC LYMPHOCYTIC LEUKEMIA USING EPIGENETIC MODIFIERS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A MALIGNANCY ARISING FROM IMMUNE CELLS (B-LYMPHOCYTES) ENDOWED WITH INTRINSIC ANTIGEN-PRESENTING CAPABILITIES. SUCH A FUNCTION HOWEVER IS LOST DURING MALIGNANT TRANSFORMATION AND CLL CELLS ARE WELL KNOWN FOR THEIR INABILITY TO PROCESS AND PRESENT ANTIGENS TO THE T-CELL ARM OF THE IMMUNE SYSTEM. INSTEAD, MALIGNANT CLL CELLS ELICIT A VAST ARRAY OF IMMUNE REGULATORY MECHANISMS CONDUCIVE TO T-CELL DYSFUNCTION AND IMMUNOSUPPRESSION. PREVIOUSLY, WE HAVE SHOWN THAT TREATMENT OF CLL CELLS WITH THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE UNLEASHED TARGET ANTIGEN EXPRESSION. HERE WE SHOW FOR THE FIRST TIME THAT COMBINING TWO EPIGENETIC MODIFIERS, 5-AZA-2'-DEOXYCYTIDINE AND THE HISTONE DEACETYLASE INHIBITOR LAQ824 EFFECTIVELY RESTORES THE IMMUNOGENICITY OF CLL CELL LINES AS WELL AS PRIMARY CELLS OBTAINED FROM CLL PATIENTS. INDEED, SUCH A COMBINATION INDUCES THE EXPRESSION OF NOVEL AND HIGHLY ANTIGENIC CANCER-TESTIS ANTIGENS (CTAS) AND COSTIMULATORY MOLECULES. THESE CHANGES FACILITATE THE FORMATION OF ROBUST SUPRAMOLECULAR ACTIVATION COMPLEXES (SMAC) BETWEEN CLL CELLS AND RESPONDER T-CELLS LEADING TO INTRACELLULAR SIGNALING, LYTIC GRANULE MOBILIZATION, AND POLARIZATION OF FUNCTIONAL AND RELEVANT T-CELL RESPONSES. THIS CASCADE OF T-CELL ACTIVATING EVENTS TRIGGERED BY CLL CELLS WITH RESTORED APC FUNCTION, POINTS TO COMBINED EPIGENETIC MODIFIER TREATMENT AS A POTENTIAL IMMUNOTHERAPEUTIC STRATEGY FOR CLL PATIENTS. 2011 15 3725 41 INHIBITION OF GLYCOGEN SYNTHASE KINASE-3 ACTIVITY LEADS TO EPIGENETIC SILENCING OF NUCLEAR FACTOR KAPPAB TARGET GENES AND INDUCTION OF APOPTOSIS IN CHRONIC LYMPHOCYTIC LEUKEMIA B CELLS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS COMMONLY DEFINED AS A DISEASE OF FAILED APOPTOSIS OF B CELLS AND REMAINS AN INCURABLE DISEASE. THE MECHANISM OF RESISTANCE TO APOPTOSIS IN CLL IS COMPLEX AND INFLUENCED BY NUMEROUS FACTORS, INCLUDING NUCLEAR FACTOR KAPPAB (NFKAPPAB)-MEDIATED EXPRESSION OF ANTIAPOPTOTIC MOLECULES. RECENT EVIDENCE INDICATES THAT GLYCOGEN SYNTHASE KINASE-3BETA (GSK-3BETA) POSITIVELY REGULATES NFKAPPAB-MEDIATED GENE TRANSCRIPTION AND CELL SURVIVAL. USING MALIGNANT B CELLS COLLECTED FROM PATIENTS WITH CLL, WE FIND THAT BOTH GSK-3BETA AND NFKAPPAB ACCUMULATE IN THE NUCLEUS OF CLL B CELLS, AND PHARMACOLOGIC INHIBITION OF GSK-3 RESULTS IN DECREASED EXPRESSION OF TWO NFKAPPAB TARGET GENES BCL-2 AND XIAP AND A SUBSEQUENT INCREASE IN CLL B-CELL APOPTOSIS EX VIVO. FURTHERMORE, WE OBSERVED THAT INHIBITION OF GSK-3 LEADS TO A DECREASE IN NFKAPPAB-MEDIATED GENE TRANSCRIPTION BUT DOES NOT AFFECT THE NUCLEAR ACCUMULATION OF NFKAPPAB IN CLL B CELLS. LAST, USING CHROMATIN IMMUNOPRECIPITATION, WE SHOW THAT GSK-3 INHIBITION ABROGATES NFKAPPAB BINDING TO ITS TARGET GENE PROMOTERS (XIAP, BCL-2), IN PART THROUGH EPIGENETIC MODIFICATION OF HISTONES. OUR RESULTS ESTABLISH THAT INHIBITION OF GSK-3 ABROGATES NFKAPPAB BINDING TO ITS TARGET GENE PROMOTERS THROUGH AN EPIGENETIC MECHANISM, ENHANCES APOPTOSIS IN CLL B CELLS EX VIVO AND IDENTIFIES GSK-3 AS A POTENTIAL THERAPEUTIC TARGET IN THE TREATMENT OF CLL. 2007 16 940 29 CHRONIC LYMPHOCYTIC LEUKEMIA AND MANTLE CELL LYMPHOMA: CROSSROADS OF GENETIC AND MICROENVIRONMENT INTERACTIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND MANTLE CELL LYMPHOMA (MCL) ARE 2 WELL-DEFINED ENTITIES THAT DIVERGE IN THEIR BASIC PATHOGENIC MECHANISMS AND CLINICAL EVOLUTION BUT THEY SHARE EPIDEMIOLOGICAL CHARACTERISTICS, CELLS OF ORIGIN, MOLECULAR ALTERATIONS, AND CLINICAL FEATURES THAT DIFFER FROM OTHER LYMPHOID NEOPLASMS. CLL AND MCL ARE CLASSICALLY CONSIDERED INDOLENT AND AGGRESSIVE NEOPLASMS, RESPECTIVELY. HOWEVER, THE CLINICAL EVOLUTION OF BOTH TUMORS IS VERY HETEROGENEOUS, WITH SUBSETS OF PATIENTS HAVING STABLE DISEASE FOR A LONG TIME WHEREAS OTHERS REQUIRE IMMEDIATE INTERVENTION. BOTH CLL AND MCL INCLUDE 2 MAJOR MOLECULAR SUBTYPES THAT SEEM TO DERIVE FROM ANTIGEN-EXPERIENCED CD5(+) B CELLS THAT RETAIN A NAIVE OR MEMORY-LIKE EPIGENETIC SIGNATURE AND CARRY A VARIABLE LOAD OF IMMUNOGLOBULIN HEAVY-CHAIN VARIABLE REGION SOMATIC MUTATIONS FROM TRULY UNMUTATED TO HIGHLY MUTATED, RESPECTIVELY. THESE 2 SUBTYPES OF TUMORS DIFFER IN THEIR MOLECULAR PATHWAYS, GENOMIC ALTERATIONS, AND CLINICAL BEHAVIOR, BEING MORE AGGRESSIVE IN NAIVE-LIKE THAN MEMORY-LIKE-DERIVED TUMORS IN BOTH CLL AND MCL. THE PATHOGENESIS OF THE 2 ENTITIES INTEGRATES THE RELEVANT INFLUENCE OF B-CELL RECEPTOR SIGNALING, TUMOR CELL MICROENVIRONMENT INTERACTIONS, GENOMIC ALTERATIONS, AND EPIGENOME MODIFICATIONS THAT CONFIGURE THE EVOLUTION OF THE TUMORS AND OFFER NEW POSSIBILITIES FOR THERAPEUTIC INTERVENTION. THIS REVIEW WILL FOCUS ON THE SIMILARITIES AND DIFFERENCES OF THESE 2 TUMORS BASED ON RECENT STUDIES THAT ARE ENHANCING THE UNDERSTANDING OF THEIR PATHOGENESIS AND CREATING SOLID BASES FOR NEW MANAGEMENT STRATEGIES. 2018 17 4693 20 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 18 5917 38 TARGETING BCL-2 IN B-CELL MALIGNANCIES AND OVERCOMING THERAPEUTIC RESISTANCE. DEFECTS IN APOPTOSIS CAN PROMOTE TUMORIGENESIS AND IMPAIR RESPONSES OF MALIGNANT B CELLS TO CHEMOTHERAPEUTICS. MEMBERS OF THE B-CELL LEUKEMIA/LYMPHOMA-2 (BCL-2) FAMILY OF PROTEINS ARE KEY REGULATORS OF THE INTRINSIC, MITOCHONDRIAL APOPTOTIC PATHWAY. OVEREXPRESSION OF ANTIAPOPTOTIC BCL-2 FAMILY PROTEINS IS ASSOCIATED WITH TREATMENT RESISTANCE AND POOR PROGNOSIS. THUS, INHIBITION OF BCL-2 FAMILY PROTEINS IS A RATIONAL THERAPEUTIC OPTION FOR MALIGNANCIES THAT ARE DEPENDENT ON ANTIAPOPTOTIC BCL-2 FAMILY PROTEINS. VENETOCLAX (ABT-199, GDC-0199) IS A HIGHLY SELECTIVE BCL-2 INHIBITOR THAT REPRESENTS THE FIRST APPROVED AGENT OF THIS CLASS AND IS CURRENTLY WIDELY USED IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AS WELL AS ACUTE MYELOID LEUKEMIA (AML). DESPITE IMPRESSIVE CLINICAL ACTIVITY, VENETOCLAX MONOTHERAPY FOR A PROLONGED DURATION CAN LEAD TO DRUG RESISTANCE OR LOSS OF DEPENDENCE ON THE TARGETED PROTEIN. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF THE MECHANISM OF ACTION OF BCL-2 INHIBITION AND THE ROLE OF THIS APPROACH IN THE CURRENT TREATMENT PARADIGM OF B-CELL MALIGNANCIES. WE SUMMARIZE THE DRIVERS OF DE NOVO AND ACQUIRED RESISTANCE TO VENETOCLAX THAT ARE CLOSELY ASSOCIATED WITH COMPLEX CLONAL SHIFTS, INTERPLAY OF EXPRESSION AND INTERACTIONS OF BCL-2 FAMILY MEMBERS, TRANSCRIPTIONAL REGULATORS, AND METABOLIC MODULATORS. WE ALSO EXAMINE HOW TUMORS INITIALLY RESISTANT TO VENETOCLAX BECOME RESPONSIVE TO IT FOLLOWING PRIOR THERAPIES. HERE, WE SUMMARIZE PRECLINICAL DATA PROVIDING A RATIONALE FOR EFFICACIOUS COMBINATION STRATEGIES OF VENETOCLAX TO OVERCOME THERAPEUTIC RESISTANCE BY A TARGETED APPROACH DIRECTED AGAINST ALTERNATIVE ANTIAPOPTOTIC BCL-2 FAMILY PROTEINS (MCL-1, BCL-XL), COMPENSATORY PROSURVIVAL PATHWAYS, EPIGENETIC MODIFIERS, AND DYSREGULATED CELLULAR METABOLISM/ENERGETICS FOR DURABLE CLINICAL REMISSIONS. 2020 19 4760 34 NOVEL TREATMENTS OF ADULT T CELL LEUKEMIA LYMPHOMA. ADULT T CELL LEUKEMIA-LYMPHOMA (ATL) IS AN AGGRESSIVE MALIGNANCY SECONDARY TO CHRONIC INFECTION WITH THE HUMAN T CELL LEUKEMIA VIRUS TYPE I (HTLV-I) RETROVIRUS. ATL CARRIES A DISMAL PROGNOSIS. ATL CLASSIFIES INTO FOUR SUBTYPES (ACUTE, LYMPHOMA, CHRONIC, AND SMOLDERING) WHICH DISPLAY DIFFERENT CLINICAL FEATURES, PROGNOSIS AND RESPONSE TO THERAPY, HENCE REQUIRING DIFFERENT CLINICAL MANAGEMENT. SMOLDERING AND CHRONIC SUBTYPES RESPOND WELL TO ANTIRETROVIRAL THERAPY USING THE COMBINATION OF ZIDOVUDINE (AZT) AND INTERFERON-ALPHA (IFN) WITH A SIGNIFICANT PROLONGATION OF SURVIVAL. CONVERSELY, THE WATCH AND WAIT STRATEGY OR CHEMOTHERAPY FOR THESE INDOLENT SUBTYPES ALLIES WITH A POOR LONG-TERM OUTCOME. ACUTE ATL IS ASSOCIATED WITH CHEMO-RESISTANCE AND DISMAL PROGNOSIS. LYMPHOMA SUBTYPES RESPOND BETTER TO INTENSIVE CHEMOTHERAPY BUT SURVIVAL REMAINS POOR. ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT) RESULTS IN LONG-TERM SURVIVAL IN ROUGHLY ONE THIRD OF TRANSPLANTED PATIENTS BUT ONLY A SMALL PERCENTAGE OF PATIENTS CAN MAKE IT TO TRANSPLANT. OVERALL, CURRENT TREATMENTS OF AGGRESSIVE ATL ARE NOT SATISFACTORY. PROGNOSIS OF REFRACTORY OR RELAPSED PATIENTS IS DISMAL WITH SOME ENCOURAGING RESULTS WHEN USING LENALIDOMIDE OR MOGAMULIZUMAB. TO OVERCOME RESISTANCE AND PREVENT RELAPSE, PRECLINICAL OR PILOT CLINICAL STUDIES USING TARGETED THERAPIES SUCH AS ARSENIC/IFN, MONOCLONAL ANTIBODIES, EPIGENETIC THERAPIES ARE PROMISING BUT WARRANT FURTHER CLINICAL INVESTIGATION. ANTI-ATL VACCINES INCLUDING TAX PEPTIDE-PULSED DENDRITIC CELLS, INDUCED TAX-SPECIFIC CTL RESPONSES IN ATL PATIENTS. FINALLY, BASED ON THE PROGRESS IN UNDERSTANDING THE PATHOPHYSIOLOGY OF ATL, AND THE RISK-ADAPTED TREATMENT APPROACHES TO DIFFERENT ATL SUBTYPES, TREATMENT STRATEGIES OF ATL SHOULD TAKE INTO ACCOUNT THE HOST IMMUNE RESPONSES AND THE HOST MICROENVIRONMENT INCLUDING HTLV-1 INFECTED NON-MALIGNANT CELLS. HEREIN, WE WILL PROVIDE A SUMMARY OF NOVEL TREATMENTS OF ATL IN VITRO, IN VIVO, AND IN EARLY CLINICAL TRIALS. 2020 20 4487 33 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