1 6780 99 [BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM ACCOMPANIED BY CHRONIC MYELOMONOCYTIC LEUKEMIA SUCCESSFULLY TREATED WITH AZACITIDINE]. BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM (BPDCN) IS A RARE DISEASE THAT DEVELOPS WITH A SKIN LESION AND IS OFTEN ACCOMPANIED BY LEUKEMIC TRANSFORMATION. THE NORMAL COUNTERPARTS OF BPDCN TUMOR CELLS ARE PROGENITORS OF PLASMACYTOID DENDRITIC CELLS, WHEREAS THE ORIGINS ARE THOUGHT TO BE HEMATOPOIETIC STEM CELLS. APPROXIMATELY 10%-20% OF BPDCN PATIENTS DEVELOP OTHER HEMATOLOGIC MALIGNANCIES, INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML). MUTATIONS IN EPIGENETIC REGULATORS ARE FREQUENTLY OBSERVED IN BOTH BPDCN AND CMML TUMORS. AZACITIDINE, A DRUG THAT TARGETS EPIGENETIC DYSREGULATION, IS KNOWN TO BE AN EFFECTIVE TREATMENT FOR CMML. HOWEVER, IT HAS BEEN USED IN FEW BPDCN PATIENTS. HERE, WE REPORT A BPDCN PATIENT WITH SKIN LESIONS, BONE MARROW INFILTRATION, AND LYMPHADENOPATHY. CMML ALSO DEVELOPED DURING THE COURSE OF BPDCN. AZACITIDINE HAD POSITIVE EFFECTS ON CMML; HOWEVER, BPDCN AGGRESSIVELY RELAPSED DURING TREATMENT. TWO TET2 MUTATIONS WERE FOUND IN BOTH BPDCN AND CMML TUMORS; ONE OF WHICH WAS COMMONLY IDENTIFIED IN BOTH TUMORS. 2018 2 1273 31 CYTOTOXIC PERIPHERAL T-CELL LYMPHOMAS AND EBV-POSITIVE T/NK-CELL LYMPHOPROLIFERATIVE DISEASES: EMERGING CONCEPTS, RECENT ADVANCES, AND THE PUTATIVE ROLE OF CLONAL HEMATOPOIESIS. A REPORT OF THE 2022 EA4HP/SH LYMPHOMA WORKSHOP. CYTOTOXIC PERIPHERAL T-CELL LYMPHOMAS AND EBV-POSITIVE T/NK-CELL LYMPHOPROLIFERATIVE DISEASES WERE DISCUSSED AT THE 2022 EUROPEAN ASSOCIATION FOR HAEMATOPATHOLOGY/SOCIETY FOR HEMATOPATHOLOGY LYMPHOMA WORKSHOP HELD IN FLORENCE, ITALY. THIS SESSION FOCUSED ON (I) PRIMARY NODAL EBV-POSITIVE T AND NK-CELL LYMPHOMAS (PRIMARY NODAL-EBV-TNKL), (II) EXTRANODAL EBV-POSITIVE T/NK LYMPHOPROLIFERATIVE DISEASES (LPD) IN CHILDREN AND ADULTS, (III) CYTOTOXIC PERIPHERAL T-CELL LYMPHOMAS, NOS (CPTCL-NOS), EBV-NEGATIVE, AND (IV) MISCELLANEOUS CASES. PRIMARY NODAL-EBV-TNKL IS A NEWLY RECOGNIZED ENTITY WHICH IS RARE, AGGRESSIVE, AND ASSOCIATED WITH UNDERLYING IMMUNE DEFICIENCY/IMMUNE DYSREGULATION. ALL CASES PRESENTED WITH LYMPHADENOPATHY BUT SOME DEMONSTRATED INVOLVEMENT OF TONSIL/WALDEYER'S RING AND EXTRANODAL SITES. THE MAJORITY OF TUMORS ARE OF T-CELL LINEAGE, AND THE MOST FREQUENT MUTATIONS INVOLVE THE EPIGENETIC MODIFIER GENES, SUCH AS TET2 AND DNMT3A, AND JAK-STAT GENES. A SPECTRUM OF EBV-POSITIVE T/NK LPD INVOLVING EXTRANODAL SITES WERE DISCUSSED AND HIGHLIGHT THE DIAGNOSTIC CHALLENGE WITH PRIMARY NODAL-EBV-TNKL WHEN THESE EXTRANODAL EBV-POSITIVE T/NK LPD CASES DEMONSTRATE PREDOMINANT NODAL DISEASE EITHER AT PRESENTATION OR DURING DISEASE PROGRESSION FROM CHRONIC ACTIVE EBV DISEASE. THE MAJORITY OF CPTCL-NOS DEMONSTRATED THE TBX21 PHENOTYPE. SOME CASES HAD A BACKGROUND OF IMMUNOSUPPRESSION OR IMMUNE DYSREGULATION. INTERESTINGLY, AN UNEXPECTED ASSOCIATION OF CPTCL-NOS, EBV-POSITIVE AND NEGATIVE, WITH TFH LYMPHOMAS/LPDS WAS OBSERVED IN THE WORKSHOP CASES. SIMILAR TO A PUBLISHED LITERATURE, THE GENETIC LANDSCAPE OF CPTCL-NOS FROM THE WORKSHOP SHOWED FREQUENT MUTATIONS IN EPIGENETIC MODIFIERS, INCLUDING TET2 AND DNMT3A, SUGGESTING A ROLE OF CLONAL HEMATOPOIESIS IN THE DISEASE PATHOGENESIS. 2023 3 5127 23 POSTMENOPAUSAL UTERINE LEIOMYOMAS AND CHRONIC LYMPHADENOPATHY: EXPLORING EPIGENETIC CHANGES AND PATHOPHYSIOLOGY. UTERINE LEIOMYOMAS (LM) ARE TUMORS ARISING FROM THE NON-NEOPLASTIC PROLIFERATION OF SMOOTH MUSCLE CELLS WITHIN THE MYOMETRIUM. LIKE BENIGN TUMORS, LM ARE NOT GENERALLY SPREAD THROUGH THE LYMPHATIC SYSTEM, AND THEREFORE SHOULD NOT BE ASSOCIATED WITH LYMPHADENOPATHY. HEREIN, WE PRESENT A CASE OF A 60-YEAR-OLD FEMALE WHO PRESENTED TO THE CLINIC WITH POSTMENOPAUSAL BLEEDING IN THE SETTING OF SONOGRAPHICALLY EVIDENT UTERINE LM AND ABDOMINAL LYMPHADENOPATHY. A LYMPH NODE BIOPSY REVEALED PLASMA CELLS AND AN EOSINOPHILIC MATERIAL PRESUMPTIVELY DIAGNOSED AS AMYLOID. SHE THEN UNDERWENT AN ABDOMINAL HYSTERECTOMY FOR DEFINITIVE TREATMENT OF LM. SURGICAL PATHOLOGY CONFIRMED THE CLINICAL DIAGNOSIS OF UTERINE AND CERVICAL LEIOMYOMA. CURRENT LITERATURE SUGGESTS THAT GENETIC AND EPIGENETIC ABNORMALITIES CONTRIBUTE TO THE PATHOGENESIS OF LM IN ADDITION TO HORMONAL SIGNALS SUCH AS ESTROGEN AND PROGESTERONE. IT IS UNUSUAL FOR LM TO OCCUR IN POST-MENOPAUSAL WOMEN DUE TO REDUCED HORMONAL INFLUENCE. THEREFORE, THIS CASE EXPLORED AN ALTERNATIVE MECHANISM OF TUMOR PROLIFERATION. THIS CASE HYPOTHESIZES THAT GENETIC MUTATIONS AND EPIGENETIC CHANGES RESULTING FROM CHRONIC INFLAMMATORY OFFENSES CONTRIBUTED TO LM GROWTH AND LYMPHADENOPATHY. 2021 4 741 27 CANDIDATE GENES OF WALDENSTROM'S MACROGLOBULINEMIA: CURRENT EVIDENCE AND RESEARCH. WALDENSTROM'S MACROGLOBULINEMIA (WM) IS A RELATIVELY UNCOMMON, INDOLENT MALIGNANCY OF IMMUNOGLOBULIN M-PRODUCING B CELLS. THE WORLD HEALTH ORGANIZATION CLASSIFIES IT AS A LYMPHOPLASMACYTIC LYMPHOMA AND PATIENTS TYPICALLY PRESENT WITH ANEMIA, HEPATOSPLENOMEGALY AND DIFFUSE LYMPHADENOPATHIES. HISTORICALLY, THE GENETIC CHARACTERIZATION OF THE DISEASE HAS BEEN HAMPERED BY THE RELATIVELY LOW PROLIFERATIVE RATE OF WM CELLS, THUS MAKING KARYOTYPING CHALLENGING. THE USE OF NOVEL TECHNOLOGIES SUCH AS FLUORESCENCE IN SITU HYBRIDIZATION, GENE ARRAY, AND WHOLE GENOME SEQUENCING HAS CONTRIBUTED GREATLY TO ESTABLISHING CANDIDATE GENES IN THE PATHOPHYSIOLOGY OF WM AND TO IDENTIFYING POTENTIAL TREATMENT TARGETS, SUCH AS L265P MYD88. THE DISCOVERY OF MICRORNAS AND THE RECOGNITION OF EPIGENETICS AS A MAJOR MODULATORY MECHANISM OF ONCOGENE EXPRESSION AND/OR ONCOSUPPRESSOR SILENCING HAVE AIDED IN FURTHER UNDERSTANDING THE PATHOGENESIS OF WM. ONCE THOUGHT TO CLOSELY RESEMBLE MULTIPLE MYELOMA, A CANCER OF TERMINALLY DIFFERENTIATED, IMMUNOGLOBULIN-SECRETING PLASMA CELLS, WM APPEARS TO GENETICALLY CLUSTER WITH OTHER INDOLENT B-CELL LYMPHOMAS SUCH AS CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL CELL LYMPHOMA. THE RELATIVE HIGH INCIDENCE OF FAMILIAL CASES OF WM AND OTHER B-CELL MALIGNANCIES HAS BEEN HELPFUL IN IDENTIFYING HIGH-RISK GENE CANDIDATES. IN THIS REVIEW, WE FOCUS ON THE ESTABLISHED GENES INVOLVED IN THE PATHOGENESIS OF WM, WITH SPECIAL EMPHASIS ON THE KEY ROLE OF DERANGEMENT OF THE NUCLEAR FACTOR KAPPA B SIGNALING PATHWAY AND EPIGENETIC MECHANISMS. 2013 5 1775 27 EBV IN T-/NK-CELL TUMORIGENESIS. EPSTEIN-BARR VIRUS (EBV), WHICH IS ASSOCIATED WITH B-CELL PROLIFERATIVE DISORDERS, ALSO TRANSFORMS T- OR NATURAL KILLER (NK)-LINEAGE CELLS AND HAS BEEN CONNECTED WITH VARIOUS T- OR NK (T/NK)-CELL MALIGNANCIES, SUCH AS EXTRANODAL NK/T-CELL LYMPHOMA-NASAL TYPE AND AGGRESSIVE NK-CELL LEUKEMIA. CHRONIC ACTIVE EBV (CAEBV) DISEASE , WHICH OCCURS MOST OFTEN IN CHILDREN AND YOUNG ADULTS IN EAST ASIA, IS AN EBV-ASSOCIATED T-/NK-CELL LYMPHOPROLIFERATIVE DISEASE. PATIENTS WITH CAEBV OFTEN PROGRESS TO OVERT LYMPHOMA OR LEUKEMIA OVER A LONG-TERM CLINICAL COURSE. EBV'S TRANSFORMING CAPACITY IN B CELLS IS WELL CHARACTERIZED, BUT THE MOLECULAR PATHOGENESIS OF CLONAL EXPANSION CAUSED BY EBV IN T/NK CELLS HAS NOT YET BEEN CLARIFIED. IN THE PRIMARY INFECTION, EBV INFECTS B CELLS AND EPITHELIAL CELLS AND MAY ALSO INFECT SOME T/NK CELLS. IN SOME INDIVIDUALS, BECAUSE OF POOR PRESENTATION BY SPECIFIC HUMAN LEUKOCYTE ANTIGENS OR THE GENETIC BACKGROUND, EBV-INFECTED T/NK CELLS EVADE HOST IMMUNITY AND SURVIVE. OCCASIONALLY, WITH THE HELP OF VIRAL ONCOGENES, EBV-ASSOCIATED T/NK LYMPHOPROLIFERATIVE DISEASES, SUCH AS CAEBV, MAY DEVELOP. THE SUBSEQUENT ACCUMULATION OF GENETIC MUTATIONS AND/OR EPIGENETIC MODIFICATIONS IN DRIVER GENES, SUCH AS DDX3X AND TP53, MAY LEAD TO OVERT LYMPHOMA AND LEUKEMIA. ACTIVATION-INDUCED CYTIDINE DEAMINASE AND THE APOBEC3 FAMILY, DRIVEN BY EBV INFECTION, MAY INDUCE CHROMOSOMAL RECOMBINATION AND SOMATIC MUTATIONS. 2018 6 5911 27 TARGETED NEXT-GENERATION SEQUENCING IN MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA AIDS DIAGNOSIS IN CHALLENGING CASES AND IDENTIFIES FREQUENT SPLICEOSOME MUTATIONS IN TRANSFORMED ACUTE MYELOID LEUKEMIA. OBJECTIVES: OPTIMAL INTEGRATION OF NEXT-GENERATION SEQUENCING (NGS) INTO CLINICAL PRACTICE IN HEMATOLOGIC MALIGNANCIES REMAINS UNCLEAR. WE EVALUATE THE UTILITY OF NGS IN MYELOID MALIGNANCIES. METHODS: A 42-GENE PANEL WAS USED TO SEQUENCE 109 CASES OF MYELODYSPLASTIC SYNDROME (MDS, N = 38), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML, N = 14), MYELOPROLIFERATIVE NEOPLASM (MPN, N = 24), AND MDS AND/OR MPN TRANSFORMED TO ACUTE MYELOID LEUKEMIA (AML, N = 33). RESULTS: AT LEAST ONE PATHOGENIC MUTATION WAS IDENTIFIED IN 74% OF CASES OF MDS, 100% OF CMMLS, AND 96% OF MPNS. IN CONTRAST, ONLY 47% OF CASES OF MDS (18/38) AND 7% (1/14) OF CMMLS EXHIBITED ABNORMAL CYTOGENETICS. IN DIAGNOSTICALLY DIFFICULT CASES OF MDS OR CMML WITH NORMAL CYTOGENETICS, NGS IDENTIFIED A PATHOGENIC MUTATION AND WAS CRITICAL IN ESTABLISHING THE CORRECT DIAGNOSIS. SPLICEOSOMAL GENES AND EPIGENETIC MODIFIERS WERE FREQUENTLY MUTATED. SPLICEOSOME MUTATIONS WERE ALSO FREQUENTLY DETECTED IN AML ARISING FROM MDS, CMML, OR MPN (39%) COMPARED WITH THE REPORTED RATE IN DE NOVO AML (7%-14%). CONCLUSIONS: IN DIFFICULT CASES OF MDS OR MPN, NGS FACILITATES DIAGNOSIS BY DETECTION OF GENE MUTATIONS TO CONFIRM CLONALITY, AND AMLS EVOLVING FROM MDS OR MPN CARRY FREQUENT MUTATIONS IN SPLICEOSOMAL GENES. 2016 7 5275 36 PROMOTER METHYLATION OF THE BONE MORPHOGENETIC PROTEIN-6 GENE IN ASSOCIATION WITH ADULT T-CELL LEUKEMIA. BONE MORPHOGENETIC PROTEINS (BMP), BELONGING TO THE TRANSFORMING GROWTH FACTOR-BETA SUPERFAMILY, ARE MULTIFUNCTIONAL REGULATORS OF CELL PROLIFERATION, DIFFERENTIATION AND APOPTOSIS IN VARIOUS TYPES OF MALIGNANT CELLS. IN THIS STUDY, WE INVESTIGATED BMP-6 PROMOTER METHYLATION IN PATIENTS WITH VARIOUS TYPES OF LEUKEMIAS. THE BMP-6 METHYLATION WAS FOUND PREFERENTIALLY IN ADULT T-CELL LEUKEMIA (ATL) (49 OF 60, 82%) COMPARED WITH OTHER TYPES OF LEUKEMIAS STUDIED INCLUDING ACUTE MYELOID LEUKEMIA (3 OF 67, 5%), ACUTE LYMPHOBLASTIC LEUKEMIA (6 OF 38, 16%) AND CHRONIC LYMPHOCYTIC LEUKEMIA (1 OF 21, 5%). AMONG SUBTYPES OF ATL, THE BMP-6 GENE WAS MORE FREQUENTLY METHYLATED IN AGGRESSIVE ATL FORMS OF ACUTE (96%) AND LYMPHOMA (94%) TYPES THAN LESS MALIGNANT CHRONIC ATL (44%) AND SMOLDERING ATL (20%). WE ALSO ANALYZED THE METHYLATION STATUS OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM HEALTHY DONORS AND NONMALIGNANT LYMPH NODES WITH REACTIVE LYMPHADENOPATHY, NONE OF WHICH SHOWED DETECTABLE BMP-6 METHYLATION IN THIS STUDY. THE BMP-6 METHYALTION WAS CORRELATED WITH DECREASED MRNA TRANSCRIPT AND PROTEIN EXPRESSION. EXPRESSION OF BMP-6 WAS RESTORED BY THE DEMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE, SUGGESTING THAT METHYLATION WAS ASSOCIATED WITH THE TRANSCRIPTIONAL SILENCING. SERIAL ANALYSIS DEMONSTRATED AN INCREASING METHYLATION OF CPG SITES IN THE BMP-6 PROMOTER AND THE RESULTANT SUPPRESSION OF BMP-6 EXPRESSION AS ATL PROGRESSED. THESE FINDINGS SUGGESTED THAT BMP-6 PROMOTER METHYLATION IS LIKELY TO BE A COMMON EPIGENETIC EVENT AT LATER STAGES OF ATL AND THAT THE METHYLATION PROFILES MAY BE USEFUL FOR THE STAGING OF ATL AS WELL AS FOR EVALUATION OF THE INDIVIDUAL RISK OF DEVELOPING THE DISEASE. 2008 8 2277 33 EPIGENETIC REGULATION BY ASXL1 IN MYELOID MALIGNANCIES. MYELOID MALIGNANCIES ARE CLONAL HEMATOPOIETIC DISORDERS THAT ARE COMPRISED OF A SPECTRUM OF GENETICALLY HETEROGENEOUS DISORDERS, INCLUDING MYELODYSPLASTIC SYNDROMES (MDS), MYELOPROLIFERATIVE NEOPLASMS (MPN), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), AND ACUTE MYELOID LEUKEMIA (AML). MYELOID MALIGNANCIES ARE CHARACTERIZED BY EXCESSIVE PROLIFERATION, ABNORMAL SELF-RENEWAL, AND/OR DIFFERENTIATION DEFECTS OF HEMATOPOIETIC STEM CELLS (HSCS) AND MYELOID PROGENITOR CELLS HEMATOPOIETIC STEM/PROGENITOR CELLS (HSPCS). MYELOID MALIGNANCIES CAN BE CAUSED BY GENETIC AND EPIGENETIC ALTERATIONS THAT PROVOKE KEY CELLULAR FUNCTIONS, SUCH AS SELF-RENEWAL, PROLIFERATION, BIASED LINEAGE COMMITMENT, AND DIFFERENTIATION. ADVANCES IN NEXT-GENERATION SEQUENCING LED TO THE IDENTIFICATION OF MULTIPLE MUTATIONS IN MYELOID NEOPLASMS, AND MANY NEW GENE MUTATIONS WERE IDENTIFIED AS KEY FACTORS IN DRIVING THE PATHOGENESIS OF MYELOID MALIGNANCIES. THE POLYCOMB PROTEIN ASXL1 WAS IDENTIFIED TO BE FREQUENTLY MUTATED IN ALL FORMS OF MYELOID MALIGNANCIES, WITH MUTATIONAL FREQUENCIES OF 20%, 43%, 10%, AND 20% IN MDS, CMML, MPN, AND AML, RESPECTIVELY. SIGNIFICANTLY, ASXL1 MUTATIONS ARE ASSOCIATED WITH A POOR PROGNOSIS IN ALL FORMS OF MYELOID MALIGNANCIES. THE FACT THAT ASXL1 MUTATIONS ARE ASSOCIATED WITH POOR PROGNOSIS IN PATIENTS WITH CMML, MDS, AND AML, POINTS TO THE POSSIBILITY THAT ASXL1 MUTATION IS A KEY FACTOR IN THE DEVELOPMENT OF MYELOID MALIGNANCIES. THIS REVIEW SUMMARIZES THE RECENT ADVANCES IN UNDERSTANDING MYELOID MALIGNANCIES WITH A SPECIFIC FOCUS ON ASXL1 MUTATIONS. 2023 9 4557 22 MUTATIONS IN ASXL1 ARE ASSOCIATED WITH POOR PROGNOSIS ACROSS THE SPECTRUM OF MALIGNANT MYELOID DISEASES. THE ASXL1 GENE IS ONE OF THE MOST FREQUENTLY MUTATED GENES IN MALIGNANT MYELOID DISEASES. THE ASXL1 PROTEIN BELONGS TO PROTEIN COMPLEXES INVOLVED IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. ASXL1 MUTATIONS ARE FOUND IN MYELOPROLIFERATIVE NEOPLASMS (MPN), MYELODYSPLASTIC SYNDROMES (MDS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND ACUTE MYELOID LEUKEMIA (AML). THEY ARE GENERALLY ASSOCIATED WITH SIGNS OF AGGRESSIVENESS AND POOR CLINICAL OUTCOME. BECAUSE OF THIS, A SYSTEMATIC DETERMINATION OF ASXL1 MUTATIONAL STATUS IN MYELOID MALIGNANCIES SHOULD HELP IN PROGNOSIS ASSESSMENT. 2012 10 4748 33 NOVEL MUTATIONS AND THEIR FUNCTIONAL AND CLINICAL RELEVANCE IN MYELOPROLIFERATIVE NEOPLASMS: JAK2, MPL, TET2, ASXL1, CBL, IDH AND IKZF1. MYELOPROLIFERATIVE NEOPLASMS (MPNS) ORIGINATE FROM GENETICALLY TRANSFORMED HEMATOPOIETIC STEM CELLS THAT RETAIN THE CAPACITY FOR MULTILINEAGE DIFFERENTIATION AND EFFECTIVE MYELOPOIESIS. BEGINNING IN EARLY 2005, A NUMBER OF NOVEL MUTATIONS INVOLVING JANUS KINASE 2 (JAK2), MYELOPROLIFERATIVE LEUKEMIA VIRUS (MPL), TET ONCOGENE FAMILY MEMBER 2 (TET2), ADDITIONAL SEX COMBS-LIKE 1 (ASXL1), CASITAS B-LINEAGE LYMPHOMA PROTO-ONCOGENE (CBL), ISOCITRATE DEHYDROGENASE (IDH) AND IKAROS FAMILY ZINC FINGER 1 (IKZF1) HAVE BEEN DESCRIBED IN BCR-ABL1-NEGATIVE MPNS. HOWEVER, NONE OF THESE MUTATIONS WERE MPN SPECIFIC, DISPLAYED MUTUAL EXCLUSIVITY OR COULD BE TRACED BACK TO A COMMON ANCESTRAL CLONE. JAK2 AND MPL MUTATIONS APPEAR TO EXERT A PHENOTYPE-MODIFYING EFFECT AND ARE DISTINCTLY ASSOCIATED WITH POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA AND PRIMARY MYELOFIBROSIS; THE CORRESPONDING MUTATIONAL FREQUENCIES ARE APPROXIMATELY 99, 55 AND 65% FOR JAK2 AND 0, 3 AND 10% FOR MPL MUTATIONS. THE INCIDENCE OF TET2, ASXL1, CBL, IDH OR IKZF1 MUTATIONS IN THESE DISORDERS RANGES FROM 0 TO 17%; THESE LATTER MUTATIONS ARE MORE COMMON IN CHRONIC (TET2, ASXL1, CBL) OR JUVENILE (CBL) MYELOMONOCYTIC LEUKEMIAS, MASTOCYTOSIS (TET2), MYELODYSPLASTIC SYNDROMES (TET2, ASXL1) AND SECONDARY ACUTE MYELOID LEUKEMIA, INCLUDING BLAST-PHASE MPN (IDH, ASXL1, IKZF1). THE FUNCTIONAL CONSEQUENCES OF MPN-ASSOCIATED MUTATIONS INCLUDE UNREGULATED JAK-STAT (JANUS KINASE/SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION) SIGNALING, EPIGENETIC MODULATION OF TRANSCRIPTION AND ABNORMAL ACCUMULATION OF ONCOPROTEINS. HOWEVER, IT IS NOT CLEAR AS TO WHETHER AND HOW THESE ABNORMALITIES CONTRIBUTE TO DISEASE INITIATION, CLONAL EVOLUTION OR BLASTIC TRANSFORMATION. 2010 11 5462 21 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 12 3871 28 JUVENILE MYELOMONOCYTIC LEUKEMIA - A BONA FIDE RASOPATHY SYNDROME. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROME WITH SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS, AGGRESSIVE FEATURES, AND POOR OUTCOMES. IN >90% OF CASES JMML IS DRIVEN BY GERMLINE OR SOMATIC MUTATIONS INVOLVING THE CANONICAL RAS PATHWAY (PTPN11, NRAS, CBL, KRAS AND NF1), WITH SOMATIC MUTATIONS/ALTERATIONS IN RAS PATHWAY GENES (SECOND HIT), SETBP1, ASXL1 AND JAK3 RESULTING IN DISEASE PROGRESSION. WHILE SPONTANEOUS REGRESSION HAS BEEN SEEN IN GERMLINE PTPN11 AND CBL MUTANT JMML, IN MOST PATIENTS, ALLOGENEIC STEM CELL TRANSPLANT IS THE ONLY CURATIVE MODALITY. JMML SHARES SEVERAL PHENOTYPIC FEATURES WITH ITS ADULT COUNTERPART PROLIFERATIVE, CHRONIC MYELOMONOCYTIC LEUKEMIA (PCMML). PCMML LARGELY OCCURS DUE TO RAS PATHWAY MUTATIONS THAT OCCUR IN THE CONTEXT OF AGE RELATED CLONAL HEMATOPOIESIS (TET2, SRSF2, ASXL1), WHILE JMML IS A BONA FIDE RASOPATHY, WITH ADDITIONAL SOMATIC MUTATIONS, INCLUDING IN EPIGENETIC REGULATORS GENES RESULTING IN DISEASE PROGRESSION. 2020 13 1040 31 CLINICAL AND GENETIC CHARACTERIZATION OF EPSTEIN-BARR VIRUS-ASSOCIATED T/NK-CELL LYMPHOPROLIFERATIVE DISEASES. BACKGROUND: EPSTEIN-BARR VIRUS (EBV)-ASSOCIATED T-/NATURAL KILLER (T/NK)-CELL LYMPHOPROLIFERATIVE DISEASES CLINICALLY TAKE ON VARIOUS FORMS, RANGING FROM AN INDOLENT COURSE TO AN AGGRESSIVE CONDITION. OBJECTIVE: CLINICALLY, FAILURE TO ESTABLISH PRECISE DIAGNOSIS AND PROVIDE PROPER TREATMENT MAKES IT DIFFICULT TO HELP PATIENTS. WE SOUGHT TO BETTER UNDERSTAND THE UNDERLYING PATHOGENESIS AND TO IDENTIFY GENETIC PROGNOSTIC FACTORS TO ACHIEVE BETTER TREATMENT EFFICACY. METHODS: IN THIS STUDY, 119 CASES OF EBV-ASSOCIATED LYMPHOPROLIFERATIVE DISEASES, INCLUDING EBV-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (N = 46) AND CHRONIC ACTIVE EBV DISEASE OF T/NK CELL TYPE (N = 73), WERE RETROSPECTIVELY EXAMINED. RESULTS: ADULTS AGED >20 YEARS AT ONSET ACCOUNTED FOR 71.4% OF OUR COHORT. ABOUT 54.6% PATIENTS WITH UNFAVORABLE OVERALL SURVIVAL DEVELOPED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND HAD HIGHER PLASMA EBV LOAD. ALLOGENIC HEMATOPOIETIC STEM-CELL TRANSPLANTATION WAS THE SOLE INDEPENDENT FAVORABLE FACTOR. WE SYSTEMATICALLY SCREENED GERMLINE AND SOMATIC ABERRATIONS BY WHOLE-EXOME AND TARGETED SEQUENCING. AMONG 372 ANTIVIRAL IMMUNITY GENES, GERMLINE VARIANTS OF 8 GENES WERE SIGNIFICANTLY ENRICHED. FROM A PANEL OF 24 DRIVER GENES, SOMATIC MUTATIONS WERE FREQUENTLY IDENTIFIED IN DOMINANT EBV-INFECTED T/NK CELLS. PATIENTS CARRYING ANY GERMLINE/SOMATIC ABERRATIONS IN EPIGENETIC MODIFIERS AND RIG-I-LIKE RECEPTOR (RLR) PATHWAY HAD WORSE OVERALL SURVIVAL THAN THOSE WITHOUT 2 TYPE ABERRATIONS. IMPORTANTLY, PATIENTS WITH IFIH1 AND/OR DDX3X ABERRATIONS IN THE RLR PATHWAY HAD HIGHER PLASMA AND NK-CELL EBV LOAD. KNOCKDOWN OF DDX3X IN NKYS CELLS DOWNREGULATED RLR SIGNALING ACTIVITIES AND ELEVATED THE EXPRESSION OF EBV-ENCODED ONCOGENES SUCH AS LMP1 AND EBNA1. CONCLUSION: GENETIC DEFECTS WERE PREVALENT IN ADULT EBV-ASSOCIATED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS PATIENTS AND PATIENTS WITH CHRONIC ACTIVE EBV DISEASE OF T/NK CELL TYPE; THESE DEFECTS WERE ASSOCIATED WITH UNFAVORABLE PROGNOSIS. THESE FINDINGS CAN HELP CLINICIANS WORK OUT MORE PRECISE STAGING OF THE CONDITION AND PROVIDE NEW INSIGHTS INTO THESE EBV-ASSOCIATED DISEASES. 2023 14 1070 29 CLONAL ARCHITECTURE OF CHRONIC MYELOMONOCYTIC LEUKEMIAS. GENOMIC STUDIES IN CHRONIC MYELOID MALIGNANCIES, INCLUDING MYELOPROLIFERATIVE NEOPLASMS (MPN), MYELODYSPLASTIC SYNDROMES (MDS), AND MPN/MDS, HAVE IDENTIFIED COMMON MUTATIONS IN GENES ENCODING SIGNALING, EPIGENETIC, TRANSCRIPTION, AND SPLICING FACTORS. IN THE PRESENT STUDY, WE INTERROGATED THE CLONAL ARCHITECTURE BY MUTATION-SPECIFIC DISCRIMINATION ANALYSIS OF SINGLE-CELL-DERIVED COLONIES IN 28 PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIAS (CMML), THE MOST FREQUENT MPN/MDS. THIS ANALYSIS REVEALS A LINEAR ACQUISITION OF THE STUDIED MUTATIONS WITH LIMITED BRANCHING THROUGH LOSS OF HETEROZYGOSITY. SERIAL ANALYSIS OF UNTREATED AND TREATED SAMPLES DEMONSTRATES A DYNAMIC ARCHITECTURE ON WHICH MOST CURRENT THERAPEUTIC APPROACHES HAVE LIMITED EFFECTS. THE MAIN DISEASE CHARACTERISTICS ARE EARLY CLONAL DOMINANCE, ARISING AT THE CD34(+)/CD38(-) STAGE OF HEMATOPOIESIS, AND GRANULOMONOCYTIC DIFFERENTIATION SKEWING OF MULTIPOTENT AND COMMON MYELOID PROGENITORS. COMPARISON OF CLONAL EXPANSIONS OF TET2 MUTATIONS IN MDS, MPN, AND CMML, TOGETHER WITH FUNCTIONAL INVALIDATION OF TET2 IN SORTED PROGENITORS, SUGGESTS A CAUSATIVE LINK BETWEEN EARLY CLONAL DOMINANCE AND SKEWED GRANULOMONOCYTIC DIFFERENTIATION. ALTOGETHER, EARLY CLONAL DOMINANCE MAY DISTINGUISH CMML FROM OTHER CHRONIC MYELOID NEOPLASMS WITH SIMILAR GENE MUTATIONS. 2013 15 1184 28 COOPERATIVE EPIGENETIC REMODELING BY TET2 LOSS AND NRAS MUTATION DRIVES MYELOID TRANSFORMATION AND MEK INHIBITOR SENSITIVITY. MUTATIONS IN EPIGENETIC MODIFIERS AND SIGNALING FACTORS OFTEN CO-OCCUR IN MYELOID MALIGNANCIES, INCLUDING TET2 AND NRAS MUTATIONS. CONCURRENT TET2 LOSS AND NRAS(G12D) EXPRESSION IN HEMATOPOIETIC CELLS INDUCED MYELOID TRANSFORMATION, WITH A FULLY PENETRANT, LETHAL CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), WHICH WAS SERIALLY TRANSPLANTABLE. TET2 LOSS AND NRAS MUTATION COOPERATIVELY LED TO DECREASE IN NEGATIVE REGULATORS OF MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) ACTIVATION, INCLUDING SPRY2, THEREBY CAUSING SYNERGISTIC ACTIVATION OF MAPK SIGNALING BY EPIGENETIC SILENCING. TET2/NRAS DOUBLE-MUTANT LEUKEMIA SHOWED PREFERENTIAL SENSITIVITY TO MAPK KINASE (MEK) INHIBITION IN BOTH MOUSE MODEL AND PATIENT SAMPLES. THESE DATA PROVIDE INSIGHTS INTO HOW EPIGENETIC AND SIGNALING MUTATIONS COOPERATE IN MYELOID TRANSFORMATION AND PROVIDE A RATIONALE FOR MECHANISM-BASED THERAPY IN CMML PATIENTS WITH THESE HIGH-RISK GENETIC LESIONS. 2018 16 4562 31 MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM OVERLAP SYNDROMES: A FOCUSED REVIEW. MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) OVERLAP SYNDROMES ARE UNIQUE MYELOID NEOPLASMS, WITH OVERLAPPING FEATURES OF MDS AND MPN. THEY CONSIST OF FOUR ADULT ONSET ENTITIES INCLUDING CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), MDS/MPN-RING SIDEROBLASTS-THROMBOCYTOSIS (MDS/MPN-RS-T), BCR-ABL1 NEGATIVE ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML) AND MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U); WITH JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) BEING THE ONLY PEDIATRIC ONSET ENTITY. AMONG THESE OVERLAP NEOPLASMS, CMML IS THE MOST FREQUENT AND IS HALLMARKED BY THE PRESENCE OF SUSTAINED PERIPHERAL BLOOD MONOCYTOSIS WITH RECURRENT MUTATIONS INVOLVING TET2 (60%), SRSF2 (50%) AND ASXL1 (40%); WITH RAS PATHWAY MUTATIONS AND JAK2V617F BEING RELATIVELY ENRICHED IN PROLIFERATIVE CMML SUBTYPES (WBC >/=13 X 109/L). CMML USUALLY PRESENTS IN THE 7TH DECADE OF LIFE, WITH A MALE PREPONDERANCE AND IS ASSOCIATED WITH A MEDIAN OVERALL SURVIVAL OF <36 MONTHS. ADVERSE PROGNOSTICATORS IN CMML INCLUDE INCREASING AGE, HIGH WBC, PRESENCE OF CIRCULATING IMMATURE MYELOID CELLS, ANEMIA, THROMBOCYTOPENIA AND TRUNCATING ASXL1 MUTATIONS. WHILE ALLOGENEIC STEM CELL TRANSPLANTATION REMAINS THE ONLY CURATIVE OPTION, GIVEN THE LATE ONSET OF THIS NEOPLASM AND HIGH FREQUENCY OF COMORBIDITIES, MOST PATIENTS REMAIN INELIGIBLE. HYPOMETHYLATING AGENTS SUCH AS AZACITIDINE, DECITABINE AND ORAL DECITABINE/CEDAZURIDINE HAVE BEEN US FDA APPROVED FOR THE MANAGEMENT OF CMML, WITH OVERALL RESPONSE RATES OF 40-50% AND COMPLETE REMISSION RATES OF <20%. WHILE THESE AGENTS EPIGENETICALLY RESTORE HEMATOPOIESIS IN A SUBSET OF RESPONDING PATIENTS, THEY DO NOT IMPACT MUTATIONAL ALLELE BURDENS AND EVENTUAL DISEASE PROGRESSION TO AML REMAINS INEVITABLE. NEWER TREATMENT MODALITIES EXPLOITING EPIGENETIC, SIGNALING AND SPLICING ABNORMALITIES COMMONLY SEEN IN CMML ARE MUCH NEEDED. 2020 17 4571 26 MYELOMONOCYTIC SKEWING IN CHRONIC MYELOMONOCYTIC LEUKEMIA: PHENOTYPIC, MOLECULAR AND BIOLOGIC FEATURES AND IMPACT ON SURVIVAL. BACKGROUND: MYELOMONOCYTIC SKEWING IS CONSIDERED AS A KEY PATHOPHYSIOLOGIC PHENOMENON IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), BUT ITS PREVALENCE AND POTENTIAL CORRELATION WITH PHENOTYPIC, GENOTYPIC, AND CLINICAL FEATURES ARE POORLY DEFINED. METHODS: SKEWED DIFFERENTIATION TOWARD THE MYELOMONOCYTIC OVER ERYTHROID COMMITMENT AS INDICATED BY AN INVERSE RATIO OF MYELOMONOCYTIC/ERYTHROID COLONIES WAS INVESTIGATED IN 146 PATIENTS WITH CMML BY SEMISOLID IN VITRO CULTURES. RESULTS: THERE WAS A HIGH PREVALENCE OF MYELOMONOCYTIC SKEWING IN PATIENTS WITH CMML (120/146, 82%); WHEREAS, THIS PHENOMENON WAS RARE IN NORMAL INDIVIDUALS (1/98, 1%). PATIENTS WITH CMML WITH MYELOMONOCYTIC SKEWING HAD HIGHER WHITE BLOOD CELL AND PERIPHERAL BLAST CELL COUNTS, AND LOWER PLATELET VALUES. THE NUMBER OF MUTATIONS IN GENES OF THE EPIGENETIC AND/OR SPLICING CATEGORY WAS HIGHER IN CMML PATIENTS WITH AS COMPARED WITH PATIENTS WITHOUT SKEWING. PATIENTS WITH MYELOMONOCYTIC SKEWING HAD MORE FREQUENTLY MUTATIONS IN RASOPATHY GENES AND HIGHER GROWTH FACTOR INDEPENDENT MYELOID COLONY FORMATION. INTERESTINGLY, THE LACK OF MYELOMONOCYTIC SKEWING DISCRIMINATED PATIENTS WITH CMML WITH A PARTICULARLY FAVORABLE PROGNOSIS (60 VS 19 MONTHS, P = .003) AND A MINIMAL RISK OF TRANSFORMATION. CONCLUSION: MYELOMONOCYTIC SKEWING AS DETERMINED BY SEMISOLID CULTURES CAN DISCRIMINATE SUBGROUPS OF PATIENTS WITH CMML WITH A DIFFERENT PHENOTYPE, A DIFFERENT GENOTYPE, AND A DIFFERENT PROGNOSIS. 2021 18 6856 31 [NOT AVAILABLE]. BIOLOGICAL ASPECTS OF JAK/STAT SIGNALING IN BCR-ABL-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS: MYELOPROLIFERATIVE DISORDERS MORE RECENTLY NAMED MYELOPROLIFERATIVE NEOPLASMS (MPN) DISPLAY SEVERAL CLINICAL ENTITIES: CHRONIC MYELOID LEUKEMIA (CML), THE CLASSICAL MPN INCLUDING POLYCYTHEMIA VERA (PV), ESSENTIAL THROMBOCYTHEMIA (ET), PRIMARY MYELOFIBROSIS (PMF) AND ATYPICAL AND UNCLASSIFIABLE NMP. THE TERM MPN IS MOSTLY USED FOR CLASSICAL BCR-ABL-NEGATIVE (MYELOPROLIFERATIVE DISORDER) (ET, PV, PMF). THESE ARE CLONAL DISEASES RESULTING FROM THE TRANSFORMATION OF AN HEMATOPOIETIC STEM CELL AND LEADING TO AN ABNORMAL PRODUCTION OF MYELOID CELLS. THE GENETIC DEFECTS RESPONSIBLE FOR THE MYELOPROLIFERATIVE ABNORMALITIES ARE CALLED << DRIVER >> MUTATIONS AND ALL RESULT IN DEREGULATION OF THE CYTOKINE RECEPTOR / JAK2 / STAT AXIS. AMONG THEM, JAK2, THE THROMBOPOIETIN RECEPTOR (MPL) AND CALRETICULIN (CALR) MUTATIONS ARE FOUND IN AROUND 90% OF THE CASES. THESE DRIVER MPN MUTATIONS CAN BE ASSOCIATED WITH OTHER DRIVER MUTATIONS ALSO FOUND IN OTHER HEMATOLOGICAL MALIGNANCIES, ESPECIALLY IN PMFS. THESE ARE CHRONIC DISEASES WITH MAJOR RISKS BEING THROMBOSIS, HEMORRHAGE AND CYTOPENIAS FOR PMF AND THE LONG-TERM PROGRESSION TO MYELOFIBROSIS AND THE TRANSFORMATION TO LEUKEMIA. MOST RECENT THERAPEUTIC HAVE FOCUSED ON TARGETING THE JAK2 SIGNALING PATHWAY DIRECTLY BY INHIBITORS OF JAK2 OR INDIRECTLY. INTERFERON A ALLOWS IN SOME CASES HEMATOLOGIC AND MOLECULAR REMISSION PATIENTS. 2016 19 2133 22 EPIGENETIC INACTIVATION OF THE MIR-34A IN HEMATOLOGICAL MALIGNANCIES. MIR-34A IS A TRANSCRIPTIONAL TARGET OF P53 AND IMPLICATED IN CARCINOGENESIS. WE STUDIED THE ROLE OF MIR-34A METHYLATION IN A PANEL OF HEMATOLOGICAL MALIGNANCIES INCLUDING ACUTE LEUKEMIA [ACUTE MYELOID LEUKEMIA (AML) AND ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)], CHRONIC LEUKEMIA [CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND CHRONIC MYELOID LEUKEMIA (CML)], MULTIPLE MYELOMA (MM) AND NON-HODGKIN'S LYMPHOMA (NHL). THE METHYLATION STATUS OF MIR-34A PROMOTER WAS STUDIED IN 12 CELL LINES AND 188 DIAGNOSTIC SAMPLES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. MIR-34A PROMOTER WAS UNMETHYLATED IN NORMAL CONTROLS BUT METHYLATED IN 75% LYMPHOMA AND 37% MYELOMA CELL LINES. HYPOMETHYLATING TREATMENT LED TO RE-EXPRESSION OF PRI-MIR-34A TRANSCRIPT IN LYMPHOMA CELLS WITH HOMOZYGOUS MIR-34A METHYLATION. IN PRIMARY SAMPLES AT DIAGNOSIS, MIR-34A METHYLATION WAS DETECTED IN 4% CLL, 5.5% MM SAMPLES AND 18.8% OF NHL AT DIAGNOSIS BUT NONE OF ALL, AML AND CML (P = 0.011). IN MM PATIENTS WITH PAIRED SAMPLES, MIR-34A METHYLATION STATUS REMAINED UNCHANGED AT PROGRESSION. AMONGST LYMPHOID MALIGNANCIES, MIR-34A WAS PREFERENTIALLY METHYLATED IN NHL (P = 0.018), IN PARTICULAR NATURAL KILLER (NK)/T-CELL LYMPHOMA. IN CONCLUSION, AMONGST HEMATOLOGICAL MALIGNANCIES, MIR-34A METHYLATION IS PREFERENTIALLY HYPERMETHYLATED IN NHL, IN PARTICULAR NK/T-CELL LYMPHOMA, IN A TUMOR-SPECIFIC MANNER, THEREFORE THE ROLE OF MIR-34A IN LYMPHOMAGENESIS WARRANTS FURTHER STUDY. 2010 20 5081 22 PI3KDELTA COORDINATES TRANSCRIPTIONAL, CHROMATIN, AND METABOLIC CHANGES TO PROMOTE EFFECTOR CD8(+) T CELLS AT THE EXPENSE OF CENTRAL MEMORY. PATIENTS WITH ACTIVATED PHOSPHATIDYLINOSITOL 3-KINASE DELTA (PI3KDELTA) SYNDROME (APDS) PRESENT WITH SINOPULMONARY INFECTIONS, LYMPHADENOPATHY, AND CYTOMEGALVIRUS (CMV) AND/OR EPSTEIN-BARR VIRUS (EBV) VIREMIA, YET WHY PATIENTS FAIL TO CLEAR CERTAIN CHRONIC VIRAL INFECTIONS REMAINS INCOMPLETELY UNDERSTOOD. USING PATIENT SAMPLES AND A MOUSE MODEL (PIK3CD(E1020K/+) MICE), WE DEMONSTRATE THAT, UPON ACTIVATION, PIK3CD(E1020K/+) CD8(+) T CELLS EXHIBIT EXAGGERATED FEATURES OF EFFECTOR POPULATIONS BOTH IN VITRO AND AFTER VIRAL INFECTION THAT ARE ASSOCIATED WITH INCREASED FAS-MEDIATED APOPTOSIS DUE TO SUSTAINED FOXO1 PHOSPHORYLATION AND FASL DEREPRESSION, ENHANCED MTORC1 AND C-MYC SIGNATURES, METABOLIC PERTURBATIONS, AND AN ALTERED CHROMATIN LANDSCAPE. CONVERSELY, PIK3CD(E1020K/+) CD8(+) CELLS FAIL TO SUSTAIN EXPRESSION OF PROTEINS CRITICAL FOR CENTRAL MEMORY, INCLUDING TCF1. STRIKINGLY, ACTIVATED PIK3CD(E1020K/+) CD8(+) CELLS EXHIBIT ALTERED TRANSCRIPTIONAL AND EPIGENETIC CIRCUITS CHARACTERIZED BY PRONOUNCED INTERLEUKIN-2 (IL-2)/STAT5 SIGNATURES AND HEIGHTENED IL-2 RESPONSES THAT PREVENT DIFFERENTIATION TO MEMORY-LIKE CELLS IN IL-15. OUR DATA POSITION PI3KDELTA AS INTEGRATING MULTIPLE SIGNALING NODES THAT PROMOTE CD8(+) T CELL EFFECTOR DIFFERENTIATION, PROVIDING INSIGHT INTO PHENOTYPES OF PATIENTS WITH APDS. 2021