1 1775 130 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 2 1040 49 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 3 5462 29 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 4 1273 43 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 5 5121 20 POSSIBLE IMPRINTING AND MICROCHIMERISM IN CHRONIC LYMPHOCYTIC LEUKEMIA AND RELATED LYMPHOPROLIFERATIVE DISORDERS. BASED ON THE CONCEPT THAT THE TUMOROGENESIS IN CHRONIC LYMPHOCYTIC LEUKAEMIA COMPRISES BOTH AN INITIAL, INHERITED MUTATION AND SUBSEQUENT SOMATIC MUTATIONS, THE PLEIOTYPIC DIVERSITY OF FAMILIAL CHRONIC LYMPHOCYTIC LEUKAEMIA AND RELATED MALIGNANT LYMPHOPROLIFERATIVE DISORDERS IS GENERALLY EXPLAINED BY A REPERTOIRE OF MONOALLELIC POLYGENES IN THE INITIAL MUTATION. EPIGENETIC GENOMIC IMPRINTING IS A LIKELY MECHANISM BEHIND OF THE ASYNCHRONEOUS REPLICATING MONOALLELIC POLYGENES WHICH IS DISCUSSED IN THE LIGHT OF PLEIOTROPHY AND BIRTH ORDER EFFECT. FURTHERMORE, IT IS DISCUSSED THAT ONE POSSIBLE MECHANISM AVAILABLE FOR THE EPIGENETIC TRANSFER OF THESE GENES COULD BE THE PHYSIOLOGICAL PREGNANCY-RELATED MICROCHIMERISM BETWEEN MOTHER AND FETUS. 2008 6 741 31 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 7 557 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 8 940 30 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 9 1078 41 CLONAL NON-MALIGNANT HEMATOLOGICAL DISORDERS: UNRAVELING MOLECULAR PATHOGENIC MECHANISMS TO DEVELOP NOVEL TARGETED THERAPEUTICS. CLONAL NON-MALIGNANT HEMATOLOGICAL DISORDERS ARE A HETEROGENEOUS GROUP OF DISEASES THAT ARE PARTICULARLY CHALLENGING FOR HEMATOLOGISTS. INDEED, MOST OBVIOUS AND FREQUENT HEMATOLOGICAL DISEASES INCLUDE A BROAD SPECTRUM OF MALIGNANCIES, SUCH AS LEUKEMIAS, LYMPHOMAS, MYELOMA, AND OTHER MYELOPROLIFERATIVE OR LYMPHOPROLIFERATIVE DISORDERS. IN RECENT YEARS, ALL THESE DISEASES HAVE BEEN CATEGORIZED BY THE WHO ACCORDING TO A NOVEL CLASSIFICATION OF MYELOID AND LYMPHOID MALIGNANCIES, WHICH TAKES IN ACCOUNT THE OUTSTANDING PROGRESS IN OUR UNDERSTANDING OF MOLECULAR DEFECTS UNDERLYING HEMATOLOGICAL MALIGNANCIES. REGARDLESS OF A NUMBER OF NOVEL TECHNOLOGIES, HEMATOLOGISTS CONTINUE TO DEAL DAILY WITH CONDITIONS WHERE A CLEAR DIAGNOSIS OF A MALIGNANCY IS MISSING: THIS IS THE CASE OF SEVERAL CLONAL HEMATOLOGICAL DISORDERS, WHICH ARE CONSIDERED BONA FIDE NON-MALIGNANT. SOME MYELODYSPLASTIC SYNDROMES, CHRONIC T AND NK DISORDERS OF GRANULAR LYMPHOCYTES, MYELOFIBROSIS, MONOCLONAL GAMMOPATHIES, MONOCLONAL B-CEL LYMPHOCYTOSIS, MASTOCYTOSIS AND PAROXYSMAL NOCTURNAL HEMOGLOBINURIA ARE PARADIGMATIC EXAMPLES OF HOW CLONAL DISORDERS ARE CLEARLY DIFFERENT FROM CANCERS, EVEN IF THEY MAY SHARE WITH HEMATOLOGICAL MALIGNANCIES SIMILAR MOLECULAR, GENETIC, EPIGENETIC AND IMMUNOLOGICAL PROCESSES. INDEED, IT IS NOT ENTIRELY CLEAR WHETHER IN INDIVIDUAL CONDITIONS SUCH PATHOGENIC MECHANISMS MAY REPRESENT INITIAL STEP(S) OF MALIGNANT TRANSFORMATION, MAKING A BRIDGE BETWEEN THESE CLONAL NON-MALIGNANT DISORDERS AND TYPICAL HEMATOLOGICAL CANCERS. SOME OF THESE NON-MALIGNANT DISORDERS IMPLY SPECIFIC PATHOGENIC MECHANISMS AND/OR CLINICAL COURSE, AND SO THEY HAVE BEEN DEFINITELY ESTABLISHED WITH THEIR OWN BIOLOGICAL AND CLINICAL IDENTITY. HOWEVER, THE OBVIOUS QUESTION WHETHER SOME OF THESE CLONAL NON-MALIGNANT HEMATOLOGICAL DISEASES FORM SOME A KIND OF DISEASE-CONTINUUM WITH THEIR CORRESPONDING MALIGNANT COUNTERPART IS STILL TO BE ANSWERED. 2014 10 5245 33 PROGNOSTIC RELEVANCE OF INTEGRATED GENETIC PROFILING IN ADULT T-CELL LEUKEMIA/LYMPHOMA. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATL) IS A HETEROGENEOUS GROUP OF PERIPHERAL T-CELL MALIGNANCIES CHARACTERIZED BY HUMAN T-CELL LEUKEMIA VIRUS TYPE-1 INFECTION, WHOSE GENETIC PROFILE HAS RECENTLY BEEN FULLY INVESTIGATED. HOWEVER, IT IS STILL POORLY UNDERSTOOD HOW THESE ALTERATIONS AFFECT CLINICAL FEATURES AND PROGNOSIS. WE INVESTIGATED THE EFFECTS OF GENETIC ALTERATIONS COMMONLY FOUND IN ATL ON DISEASE PHENOTYPES AND CLINICAL OUTCOMES, BASED ON GENOTYPING DATA OBTAINED FROM 414 AND 463 ATL PATIENTS USING TARGETED-CAPTURE SEQUENCING AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAY KARYOTYPING, RESPECTIVELY. AGGRESSIVE (ACUTE/LYMPHOMA) SUBTYPES WERE ASSOCIATED WITH AN INCREASED BURDEN OF GENETIC AND EPIGENETIC ALTERATIONS, HIGHER FREQUENCIES OF TP53 AND IRF4 MUTATIONS, AND MANY COPY NUMBER ALTERATIONS (CNAS), INCLUDING PD-L1 AMPLIFICATIONS AND CDKN2A DELETIONS, COMPARED WITH INDOLENT (CHRONIC/SMOLDERING) SUBTYPES. BY CONTRAST, STAT3 MUTATIONS WERE MORE CHARACTERISTIC OF INDOLENT ATL. HIGHER NUMBERS OF SOMATIC MUTATIONS AND CNAS SIGNIFICANTLY CORRELATED WITH WORSE SURVIVAL. IN A MULTIVARIATE ANALYSIS INCORPORATING BOTH CLINICAL FACTORS AND GENETIC ALTERATIONS, THE JAPAN CLINICAL ONCOLOGY GROUP PROGNOSTIC INDEX HIGH-RISK, OLDER AGE, PRKCB MUTATIONS, AND PD-L1 AMPLIFICATIONS WERE INDEPENDENT POOR PROGNOSTIC FACTORS IN AGGRESSIVE ATL. IN INDOLENT ATL, IRF4 MUTATIONS, PD-L1 AMPLIFICATIONS, AND CDKN2A DELETIONS WERE SIGNIFICANTLY ASSOCIATED WITH SHORTER SURVIVAL, ALTHOUGH THE CHRONIC SUBTYPE WITH UNFAVORABLE CLINICAL FACTORS WAS ONLY MARGINALLY SIGNIFICANT. THUS, SOMATIC ALTERATIONS CHARACTERIZING AGGRESSIVE DISEASES PREDICT WORSE PROGNOSIS IN INDOLENT ATL, AMONG WHICH PD-L1 AMPLIFICATIONS ARE A STRONG GENETIC PREDICTOR IN BOTH AGGRESSIVE AND INDOLENT ATL. ATL SUBTYPES ARE FURTHER CLASSIFIED INTO MOLECULARLY DISTINCT SUBSETS WITH DIFFERENT PROGNOSIS. GENETIC PROFILING MIGHT CONTRIBUTE TO IMPROVED PROGNOSTICATION AND MANAGEMENT OF ATL PATIENTS. 2018 11 941 28 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 12 5512 31 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 13 1044 43 CLINICAL CHARACTERISTICS OF HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ASSOCIATED WITH NON-HODGKIN B-CELL LYMPHOMA: A MULTICENTER RETROSPECTIVE STUDY. BACKGROUND: HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ASSOCIATED WITH B-CELL LYMPHOMA IS A HIGHLY AGGRESSIVE DISEASE WITH UNCLEAR CLINICAL FEATURES AND HAS NO STANDARD TREATMENT. PATIENTS AND METHODS: WE ANALYZED THE CLINICAL CHARACTERISTICS OF 31 PATIENTS FROM TWO INDIVIDUAL CENTERS. RESULTS: THE MEDIAN OVERALL SURVIVAL WAS ONLY 1.5 MONTHS. BOTH UNIVARIATE AND MULTIVARIATE ANALYSES, BASED ON LYMPHOMA OR HLH-RELATED CHARACTERISTICS, REVEALED THAT PATIENTS WITH HIGH EPSTEIN-BARR VIRUS (EBV) DNA LOAD AND >/= 2 EXTRANODAL LESIONS, OR HYPOFIBRINOGENEMIA, RESPECTIVELY, SHOWED SIGNIFICANTLY POORER OVERALL SURVIVAL. INTERESTINGLY, SOME PATIENTS WITH HIGH EBV DNA LOAD HAD EBV-POSITIVE NATURAL KILLER (NK) AND/OR T CELLS, WHICH MAY BE RELATED TO THE COEXISTENCE OF IMMUNODEFICIENCY AND/OR CHRONIC ACTIVE EBV INFECTION. MOLECULAR GENETICS EXAMINATION CONFIRMED THAT 47.4% (9/19) OF PATIENTS HAD COMPLEX KARYOTYPES, 37.5% (3/8) OF PATIENTS HAD TP53 DELETIONS, AND 21.34% (3/14) OF PATIENTS HAD TP53 MUTATION OR ALTERATION OF MALIGNANCY-RELATED PATHWAYS, INCLUDING BCR/NF-KAPPAB, JAK-STAT, AND EPIGENETIC REGULATORY PATHWAYS, WHICH MAY PROVIDE CLUES TO CHOOSE TARGETS FOR THERAPY. TREATMENT REGIMENS CONTAINING ETOPOSIDE, ANTI-CD20 MONOCLONAL ANTIBODIES, OR ANTHRACYCLINES IMPROVED PATIENT PROGNOSIS (P = .0183, .025, AND .0436, RESPECTIVELY). PATIENTS WITH INFECTIONS HAD SIGNIFICANTLY SHORTER SURVIVAL THAN THOSE WITHOUT INFECTIONS (P = .00019). CONCLUSION: THE PATIENTS' PERFORMANCE STATUS, NUMBER OF EXTRANODAL LESIONS, HIGH EBV DNA LOAD, AND HYPOFIBRINOGENEMIA ARE POOR PROGNOSTIC FACTORS FOR HLH ASSOCIATED WITH B-CELL LYMPHOMA. MOLECULAR GENETIC HIGH-RISK FACTORS ARE OF PARTICULAR IMPORTANCE BECAUSE THESE FACTORS CAN PROVIDE INFORMATION FOR PROGNOSIS PREDICTION, TREATMENT DECISIONS, AND DISEASE SURVEILLANCE. 2021 14 867 42 CHRONIC ACTIVE EPSTEIN-BARR VIRUS INFECTION OF T/NK-CELL TYPE MIMICKING CLASSIC HODGKIN LYMPHOMA: CLINICOPATHOLOGIC AND GENETIC FEATURES OF 8 CASES SUPPORTING A VARIANT WITH "HODGKIN/REED-STERNBERG-LIKE" CELLS OF NK PHENOTYPE. CHRONIC ACTIVE EPSTEIN-BARR VIRUS (EBV) INFECTION OF T-CELL AND NK-CELL TYPE, SYSTEMIC FORM (CAEBV-T/NK-S) IS CHARACTERIZED BY EBV T-CELL AND/OR NK-CELL PROLIFERATION WITH NO CHANGES SUGGESTING MALIGNANCY. THEREFORE, WHEN HODGKIN/REED-STERNBERG (HRS)-LIKE CELLS ARE SCATTERED IN CAEBV-T/NK-S, IT IS MORE LIKELY TO BE MISDIAGNOSED AS CLASSIC HODGKIN LYMPHOMA. WE ENCOUNTERED A CASE WHEREIN THE PATIENT SHOWED HRS-LIKE CELLS WITH TYPICAL NK PHENOTYPE. THEREFORE, WE FURTHER INVESTIGATED 8 SIMILAR CASES TO PROVIDE CLINICOPATHOLOGIC AND GENETIC FEATURES AND DISCUSS THEIR DISTINCTION FROM OTHER RELATED DISEASES. CLINICALLY, ALL CASES MET THE DIAGNOSTIC CRITERIA OF CAEBV. MOREOVER, 4/8 PATIENTS HAD HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS. THE MEDIAN SURVIVAL WAS 16 MONTHS (RANGE, 5 TO 35 MO). PATHOLOGICALLY, ALL LYMPH NODE SAMPLES HAD A REMARKABLY SIMILAR MORPHOLOGY WITH SCATTERED HRS-LIKE CELLS SURROUNDED BY A MIXTURE OF SMALL-SIZED LYMPHOCYTES, PLASMA CELLS, AND MACROPHAGES THAT MASQUERADED CLASSIC HODGKIN LYMPHOMA. BESIDES, ERYTHROPHAGOCYTOSIS WAS DETECTED IN 4/11 SAMPLES. THE HRS-LIKE CELLS WERE POSITIVE FOR CD2, CD3P, CD30, CD56, GRB, AND EBER-ISH, BUT NEGATIVE FOR CD20, CD5, PAX-5, AND LMP-1. THE SURROUNDING LYMPHOCYTES WERE MAINLY CD8 CYTOTOXIC T CELLS, WITHOUT OBVIOUS ABERRANT EXPRESSION. IN ADDITION, ALL PATIENTS WERE POLYCLONAL IN THE T-CELL RECEPTOR GAMMA REARRANGEMENT TEST. THE HARBORED MUTATIONS WERE MAINLY IN EPIGENETIC MODIFIERS, JAK-STAT SIGNALING PATHWAY, AND APOPTOSIS/CELL CYCLE PATHWAY, INCLUDING SOCS1, DDX3X, AND KMT2D, SIMILAR TO OTHER EBV-ASSOCIATED T/NK-CELL LYMPHOPROLIFERATIVE DISORDERS. THEREFORE, THE EVIDENCE INDICATES THAT "HRS-LIKE CELLS OF NK PHENOTYPE" IS A VARIANT OF CAEBV-T/NK-S. THIS STUDY MAY RAISE AWARENESS OF SUCH CONFOUNDING CAEBV-T/N-S CASES IN CLINICAL PRACTICE TO AVOID MISDIAGNOSIS AND TREATMENT DELAY. 2019 15 2992 26 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 16 2133 23 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 17 4760 36 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 18 6373 24 THE ROLE OF MIRNAS AND EPIGENETIC MECHANISMS IN PRIMARY GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA. GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA IS A RARE LOW-GRADE B-CELL NON-HODGKIN LYMPHOMA ASSOCIATED WITH HELICOBACTER PYLORI INFECTION AND THE SUBSEQUENT CHRONIC INFLAMMATION. SIGNIFICANT PROGRESS IN UNDERSTANDING THE PATHOGENESIS OF THE DISEASE HAS ALREADY BEEN MADE. HOWEVER, THE EXACT MOLECULAR PATHWAYS OF LYMPHOMAGENESIS REMAIN UNCLEAR. FURTHERMORE, DIFFICULTIES REGARDING ACCURATE DIAGNOSIS OF GASTRIC MALT LYMPHOMA AND ITS DISCRIMINATION FROM GASTRITIS OR OTHER LYMPHOMA SUBTYPES ARISE. RECENT STUDIES EVALUATE THE ROLE OF MIRNAS AND EPIGENETIC ALTERATIONS ON MALT LYMPHOMA PATHOGENESIS AND PROGNOSIS. THIS REVIEW CRITICALLY SUMMARIZES THE MOST IMPORTANT DATA ON THE ROLE OF MIRNAS AND EPIGENETICS IN MALT LYMPHOMAS PATHOGENESIS, PROGNOSIS AND TREATMENT. 2016 19 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 20 6590 36 TUMOR SUPPRESSOR INACTIVATION IN THE PATHOGENESIS OF ADULT T-CELL LEUKEMIA. TUMOR SUPPRESSOR FUNCTIONS ARE ESSENTIAL TO CONTROL CELLULAR PROLIFERATION, TO ACTIVATE THE APOPTOSIS OR SENESCENCE PATHWAY TO ELIMINATE UNWANTED CELLS, TO LINK DNA DAMAGE SIGNALS TO CELL CYCLE ARREST CHECKPOINTS, TO ACTIVATE APPROPRIATE DNA REPAIR PATHWAYS, AND TO PREVENT THE LOSS OF ADHESION TO INHIBIT INITIATION OF METASTASES. THEREFORE, TUMOR SUPPRESSOR GENES ARE INDISPENSABLE TO MAINTAINING GENETIC AND GENOMIC INTEGRITY. CONSEQUENTLY, INACTIVATION OF TUMOR SUPPRESSORS BY SOMATIC MUTATIONS OR EPIGENETIC MECHANISMS IS FREQUENTLY ASSOCIATED WITH TUMOR INITIATION AND DEVELOPMENT. IN CONTRAST, REACTIVATION OF TUMOR SUPPRESSOR FUNCTIONS CAN EFFECTIVELY REVERSE THE TRANSFORMED PHENOTYPE AND LEAD TO CELL CYCLE ARREST OR DEATH OF CANCEROUS CELLS AND BE USED AS A THERAPEUTIC STRATEGY. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATLL) IS AN AGGRESSIVE LYMPHOPROLIFERATIVE DISEASE ASSOCIATED WITH INFECTION OF CD4 T CELLS BY THE HUMAN T-CELL LEUKEMIA VIRUS TYPE 1 (HTLV-I). HTLV-I-ASSOCIATED T-CELL TRANSFORMATION IS THE RESULT OF A MULTISTEP ONCOGENIC PROCESS IN WHICH THE VIRUS INITIALLY INDUCES CHRONIC T-CELL PROLIFERATION AND ALTERS CELLULAR PATHWAYS RESULTING IN THE ACCUMULATION OF GENETIC DEFECTS AND THE DEREGULATED GROWTH OF VIRALLY INFECTED CELLS. THIS REVIEW WILL FOCUS ON THE CURRENT KNOWLEDGE OF THE GENETIC AND EPIGENETIC MECHANISMS REGULATING THE INACTIVATION OF TUMOR SUPPRESSORS IN THE PATHOGENESIS OF HTLV-I. 2015