1 5663 95 SEZARY SYNDROME COEXISTING WITH B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA: CASE REPORT AND REVIEW OF THE LITERATURE. INTRODUCTION: THE SIMULTANEOUS PRESENTATION OF CHRONIC B-CELL LYMPHOCYTIC LEUKEMIA (B-CLL) AND CUTANEOUS T-CELL LYMPHOMA (CTCL) IS EXTREMELY RARE. CASE REPORT: WE DESCRIBE A PATIENT WITH B-CLL AND SEZARY SYNDROME (SS), AN ERYTHRODERMIC AND LEUKEMIC VARIANT OF CTCL. DESPITE TREATMENT, THE SS PROGRESSED TO INVOLVE INTERNAL ORGANS AND EVENTUAL DEATH OF THE PATIENT FROM SEPSIS. THIS IS THE FIRST REPORTED CASE OF SS COEXISTING WITH CHRONIC LYMPHOCYTIC LEUKEMIA IN WHICH AN ANTI-V BETA 13.6 ANTIBODY WAS USED TO SERIALLY TRACK CHANGES IN CIRCULATING NEOPLASTIC T CELLS VIS-A-VIS NEOPLASTIC B CELLS AND TO DETECT NEOPLASTIC T CELLS IN ASCITIC FLUID NEAR THE END OF THE PATIENT'S LIFE. DISCUSSION: WE SPECULATE THAT THE COEXISTENCE OF B-CLL AND CTCL IS THE RESULT OF AN INITIATING GENETIC OR EPIGENETIC DEFECT AT THE LEVEL OF THE COMMON LYMPHOID STEM CELL THAT PREDISPOSES BOTH B-CELL AND T-CELL LINEAGES TO ADDITIONAL ONCOGENIC CHANGES AT A MORE ADVANCED STAGE OF DIFFERENTIATION. 2008 2 2935 26 GENETIC ALTERATION ASSOCIATED WITH CHRONIC LYMPHOCYTIC LEUKEMIA. THE GENETICS OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) DIFFER CONSIDERABLY FROM MOST OTHER FORMS OF HEMATOLOGIC MALIGNANCY WHICH ARE USUALLY CHARACTERIZED BY CHROMOSOME TRANSLOCATIONS. B-CLL TYPICALLY CONTAINS CHROMOSOMAL DELETIONS AND CHROMOSOMES 13Q14 AND 11Q22-->Q23 ARE THE MOST COMMON. THESE TWO REGIONS APPEAR TO SHARE A COMMON ANCESTRAL ORIGIN (AUER ET AL., 2007B). OVERALL, CHROMOSOMAL ABNORMALITIES CAN BE FOUND IN THE MAJORITY OF PATIENTS WITH B-CLL WHEN USING SENSITIVE TECHNIQUES (DOHNERET AL., 2000) AND POSSIBLY REFLECTS AN UNDERLYING PREDISPOSITION, WITH A SMALL BUT SIGNIFICANT NUMBER OF FAMILIAL CASES. ALTHOUGH SINGLE AND CONSISTENT ABNORMALITIES ARE MOST COMMON, MULTIPLE REARRANGEMENTS CAN OCCUR, OFTEN WITH DISEASE PROGRESSION (FEGANETAL., 1995; DOHNER ET AL., 2000). REGIONS OF RECURRENT DELETION SUGGEST THE PRESENCE OF TUMOR SUPPRESSOR GENES IF FOLLOWING KNUDSON'S THEORETICAL 2-HIT MODEL. HOWEVER, DESPITE EXTENSIVE SEQUENCING ANALYSIS OVER THE LAST DECADE AND LACK OF PATHOGENIC MUTATIONS IDENTIFIED, THERE HAS BEEN A MOVE AWAY FROM THIS SUGGESTED HYPOTHESIS AND ALTERNATIVE MECHANISMS OF GENE INACTIVATION INVOLVING EPIGENETIC SILENCING OR HAPLOINSUFFICIENCY MAY BE CONSIDERED AS MORE LIKELY IN THIS DISEASE. THIS REVIEW FOCUSES ON THE COMMON GENETIC ABNORMALITIES IN B-CLL AND RELATES THEM TO SOME OF THE MORE RECENT HYPOTHESES ON INACTIVATION OF GENES WITHIN THESE REGIONS OF DELETION. 2007 3 5899 31 T-CELL DYSFUNCTION IN CHRONIC LYMPHOCYTIC LEUKEMIA FROM AN EPIGENETIC PERSPECTIVE. CELLULAR IMMUNOTHERAPEUTIC APPROACHES SUCH AS CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELL THERAPY IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) THUS FAR HAVE NOT MET THE HIGH EXPECTATIONS. THEREFORE IT IS ESSENTIAL TO BETTER UNDERSTAND THE MOLECULAR MECHANISMS OF CLLINDUCED T-CELL DYSFUNCTION. EVEN THOUGH A SIGNIFICANT NUMBER OF STUDIES ARE AVAILABLE ON T-CELL FUNCTION AND DYSFUNCTION IN CLL PATIENTS, NONE EXAMINE DYSFUNCTION AT THE EPIGENOMIC LEVEL. IN NON-MALIGNANT T-CELL RESEARCH, EPIGENOMICS IS WIDELY EMPLOYED TO DEFINE THE DIFFERENTIATION PATHWAY INTO T-CELL EXHAUSTION. ADDITIONALLY, METABOLIC RESTRICTIONS IN THE TUMOR MICROENVIRONMENT THAT CAUSE T-CELL DYSFUNCTION ARE OFTEN MEDIATED BY EPIGENETIC CHANGES. WITH THIS REVIEW PAPER WE ARGUE THAT UNDERSTANDING THE EPIGENETIC (DYS)REGULATION IN T CELLS OF CLL PATIENTS SHOULD BE LEVELED TO THE KNOWLEDGE WE CURRENTLY HAVE OF THE NEOPLASTIC B CELLS THEMSELVES. THIS WILL PERMIT A COMPLETE UNDERSTANDING OF HOW THESE IMMUNE CELL INTERACTIONS REGULATE T- AND B-CELL FUNCTION. HERE WE RELATE THE CELLULAR AND PHENOTYPIC CHARACTERISTICS OF CLL-INDUCED T-CELL DYSFUNCTION TO EPIGENETIC STUDIES OF T-CELL REGULATION EMERGING FROM CHRONIC VIRAL INFECTION AND TUMOR MODELS. THIS PAPER PROPOSES A FRAMEWORK FOR FUTURE STUDIES INTO THE EPIGENETIC REGULATION OF CLL-INDUCED TCELL DYSFUNCTION, KNOWLEDGE THAT WILL HELP TO GUIDE IMPROVEMENTS IN THE UTILITY OF AUTOLOGOUS T-CELL BASED THERAPIES IN CLL. 2021 4 230 24 ADAPTIVE AND INNATE CYTOTOXIC EFFECTORS IN CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) SUBJECTS WITH STABLE DISEASE. CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) IS CHARACTERISED BY THE EXPANSION OF A NEOPLASTIC MATURE B CELL CLONE. CLL CLINICAL OUTCOME IS VERY HETEROGENEOUS, WITH SOME SUBJECTS NEVER REQUIRING THERAPY AND SOME SHOWING AN AGGRESSIVE DISEASE. GENETIC AND EPIGENETIC ALTERATIONS AND PRO-INFLAMMATORY MICROENVIRONMENT INFLUENCE CLL PROGRESSION AND PROGNOSIS. THE INVOLVEMENT OF IMMUNE-MEDIATED MECHANISMS IN CLL CONTROL NEEDS TO BE INVESTIGATED. WE ANALYSE THE ACTIVATION PROFILE OF INNATE AND ADAPTIVE CYTOTOXIC IMMUNE EFFECTORS IN A COHORT OF 26 CLL PATIENTS WITH STABLE DISEASE, AS KEY ELEMENTS FOR IMMUNE-MEDIATED CONTROL OF CANCER PROGRESSION. WE OBSERVED AN INCREASE IN CD54 EXPRESSION AND INTERFERON (IFN)-GAMMA PRODUCTION BY CYTOTOXIC T CELLS (CTL). CTL ABILITY TO RECOGNISE TUMOUR-TARGETS DEPENDS ON HUMAN LEUKOCYTE ANTIGENS (HLA)-CLASS I EXPRESSION. WE OBSERVED A DECREASED EXPRESSION OF HLA-A AND HLA-BC ON B CELLS OF CLL SUBJECTS, ASSOCIATED WITH A SIGNIFICANT REDUCTION IN INTRACELLULAR CALNEXIN THAT IS RELEVANT FOR HLA SURFACE EXPRESSION. NATURAL KILLER (NK) CELLS AND CTL FROM CLL SUBJECTS SHOW AN INCREASED EXPRESSION OF THE ACTIVATING RECEPTOR KIR2DS2 AND A REDUCTION OF 3DL1 AND NKG2A INHIBITING MOLECULES. THEREFORE, AN ACTIVATION PROFILE CHARACTERISES CTL AND NK CELLS OF CLL SUBJECTS WITH STABLE DISEASE. THIS PROFILE IS CONCEIVABLE WITH THE FUNCTIONAL INVOLVEMENT OF CYTOTOXIC EFFECTORS IN CLL CONTROL. 2023 5 2469 16 EPIGENETIC TRAJECTORIES OF THE PREMALIGNANT-TO-MALIGNANT TRANSITION OF CHRONIC LYMPHOCYTIC LEUKEMIA. KRETZMER AND COLLEAGUES SHOW THAT THE TRANSITION TO ALTERED METHYLOME OCCURS VERY EARLY IN CHRONIC LYMPHOCYTIC LEUKEMIA, AND ONCE ACQUIRED, IT IS A CLONAL AND EXTREMELY STABLE CHANGE. HOWEVER, THE PRECISE TIME POINT WHEN THE LEUKEMIC CLONE STARTS DEVIATING SIGNIFICANTLY FROM THE NORMAL B-CELL DIFFERENTIATION TRAJECTORY IS STILL ELUSIVE. SEE RELATED ARTICLE BY KRETZMER ET AL., P. 54. 2021 6 5141 20 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 7 3902 24 LEARNING FROM THE FAILURES OF DRUG DISCOVERY IN B-CELL NON-HODGKIN LYMPHOMAS AND PERSPECTIVES FOR THE FUTURE: CHRONIC LYMPHOCYTIC LEUKEMIA AND DIFFUSE LARGE B-CELL LYMPHOMA AS TWO ENDS OF A SPECTRUM IN DRUG DEVELOPMENT. DESPITE SUBSTANTIAL RECENT ADVANCES, THERE IS STILL AN UNMET NEED FOR BETTER THERAPIES IN B-CELL NON HODGKIN LYMPHOMAS (B-NHL), ESPECIALLY IN RELAPSED OR REFRACTORY DISEASE. MANY NOVEL TARGETED DRUGS HAVE BEEN DEVELOPED BASED ON A BETTER MOLECULAR UNDERSTANDING OF B-NHL. AREAS COVERED: THIS ARTICLE FOCUSES ON CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AS A REPRESENTATIVE FOR INDOLENT LYMPHOMAS AND PARADIGMATIC FOR THE TREMENDOUS PROGRESS IN TREATING B-NHL ON THE ONE HAND AND DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) AS A REPRESENTATIVE FOR AGGRESSIVE LYMPHOMAS AND PARADIGMATIC FOR MANY UNSOLVED PROBLEMS IN LYMPHOMA TREATMENT OR THE OTHER HAND. WE HIGHLIGHT SALIENT POINTS IN CURRENT THERAPIES TARGETING GENETIC, EPIGENETIC, IMMUNOLOGICAL AND MICROENVIRONMENTAL ALTERATIONS. POSSIBLE REASONS FOR DRUG FAILURE IN CLINICAL TRIALS LIKE TUMOR HETEROGENEITY, CLONAL EVOLUTION AND DRUG RESISTANCE MECHANISMS ARE DISCUSSED. BASED THEREON, SOME PERSPECTIVES FOR FURTHER DRUG DISCOVERY ARE GIVEN. EXPERT OPINION: IN VIEW OF THE PATHOGENETIC COMPLEXITY OF LYMPHOMAS, THERAPIES TARGETING EXCLUSIVELY A SINGLE ALTERATION MAY FAIL BECAUSE RESISTANCE MECHANISMS ARE PRESENT EITHER INITIALLY OR EVOLVE DURING TREATMENT. THEREFORE, FUTURE THERAPIES IN B-NHL MAY HAVE TO TARGET THE GREATEST POSSIBLE NUMBER OF GENETIC, IMMUNOLOGICAL OR EPIGENETIC ALTERATIONS STILL ALLOWING TOLERABILITY AND TO MONITOR THESE ALTERATIONS DURING THERAPY. 2017 8 6222 17 THE LANDSCAPE OF SOMATIC MUTATIONS IN LYMPHOBLASTOID CELL LINES. SOMATIC MUTATIONS HAVE IMPORTANT BIOLOGICAL RAMIFICATIONS WHILE EXERTING SUBSTANTIAL RATE, TYPE, AND GENOMIC LOCATION HETEROGENEITY. YET, THEIR SPORADIC OCCURRENCE MAKES THEM DIFFICULT TO STUDY AT SCALE AND ACROSS INDIVIDUALS. LYMPHOBLASTOID CELL LINES (LCLS), A MODEL SYSTEM FOR HUMAN POPULATION AND FUNCTIONAL GENOMICS, HARBOR LARGE NUMBERS OF SOMATIC MUTATIONS AND HAVE BEEN EXTENSIVELY GENOTYPED. BY COMPARING 1,662 LCLS, WE REPORT THAT THE MUTATIONAL LANDSCAPE OF THE GENOME VARIES ACROSS INDIVIDUALS IN TERMS OF THE NUMBER OF MUTATIONS, THEIR GENOMIC LOCATIONS, AND THEIR SPECTRA; THIS VARIATION MAY ITSELF BE MODULATED BY SOMATIC TRANS-ACTING MUTATIONS. MUTATIONS ATTRIBUTED TO THE TRANSLESION DNA POLYMERASE ETA FOLLOW TWO DIFFERENT MODES OF FORMATION, WITH ONE MODE ACCOUNTING FOR THE HYPERMUTABILITY OF THE INACTIVE X CHROMOSOME. NONETHELESS, THE DISTRIBUTION OF MUTATIONS ALONG THE INACTIVE X CHROMOSOME APPEARS TO FOLLOW AN EPIGENETIC MEMORY OF THE ACTIVE FORM. 2023 9 3316 30 HISTIOCYTIC SARCOMA AS A SECONDARY MALIGNANCY: PATHOBIOLOGY, DIAGNOSIS, AND TREATMENT. HISTIOCYTIC SARCOMA (HS) IS AN EXTREMELY RARE NON-LANGERHANS CELL DISORDER WITH AN AGGRESSIVE COURSE AND LIMITED TREATMENT OPTIONS. RECENT ADVANCES IN MOLECULAR/GENETIC SEQUENCING HAVE SUGGESTED A COMMON CLONAL ORIGIN BETWEEN VARIOUS HEMATOLYMPHOID DISORDERS AND CASES OF SECONDARY HS. DERIVING CONCLUSIONS FROM PREVIOUSLY REPORTED CASES OF HS ARISING SECONDARILY TO CERTAIN HEMATOLYMPHOID DISORDERS, HERE WE HAVE TRIED TO PROVIDE INSIGHT INTO THE MECHANISMS INFLUENCING THIS EVOLUTION. WE ALSO DISCUSS A CLINICAL CASE OF A 72-YEAR-OLD MAN WITH A DIAGNOSIS OF CHRONIC MYELOID LEUKEMIA (CML), PRESENTING SUBSEQUENTLY WITH A HETEROGENEOUS LIVER MASS POSITIVE WITH A DIAGNOSIS OF HS. THE LIVER MASS SHOWED A RETAINED BCR-ABL1 TRANSLOCATION SUGGESTING CLONALITY BETWEEN THE CML AND HS. AS SEEN IN OUR CASE AND OTHER REPORTED CASES OF HS DERIVED SECONDARILY, THE CONCURRENT EXPRESSION OF IMMUNOGLOBULIN HEAVY (IGH)-/LIGHT-CHAIN REARRANGEMENTS OR CYTOGENETIC MARKERS COMMON TO THE PRIMARY MALIGNANCY SUGGESTS AN EVOLUTIONARY MECHANISM INVOLVING LINEAGE SWITCHING THAT COULD POTENTIALLY BE INFLUENCED BY GENETIC OR EPIGENETIC CUES WHICH MAY OCCUR AT THE LEVEL OF A PROGENITOR OR THE MALIGNANT CELL ITSELF. 2016 10 1260 22 CURRENT VIEWS ON THE INTERPLAY BETWEEN TYROSINE KINASES AND PHOSPHATASES IN CHRONIC MYELOID LEUKEMIA. CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE DISORDER CHARACTERIZED BY BCR-ABL1 ONCOGENE EXPRESSION. THIS DYSREGULATED PROTEIN-TYROSINE KINASE (PTK) IS KNOWN AS THE PRINCIPAL DRIVER OF THE DISEASE AND IS TARGETED BY TYROSINE KINASE INHIBITORS (TKIS). EXTENSIVE DOCUMENTATION HAS ELUCIDATED HOW THE TRANSFORMATION OF MALIGNANT CELLS IS CHARACTERIZED BY MULTIPLE GENETIC/EPIGENETIC CHANGES LEADING TO THE LOSS OF TUMOR-SUPPRESSOR GENES FUNCTION OR PROTO-ONCOGENES EXPRESSION. THE IMPAIRMENT OF ADEQUATE LEVELS OF SUBSTRATES PHOSPHORYLATION, THUS AFFECTING THE BALANCE PTKS AND PROTEIN PHOSPHATASES (PPS), REPRESENTS A WELL-ESTABLISHED CELLULAR MECHANISM TO ESCAPE FROM SELF-LIMITING SIGNALS. IN THIS REVIEW, WE FOCUS OUR ATTENTION ON THE CHARACTERIZATION OF AND INTERACTIONS BETWEEN PTKS AND PPS, EMPHASIZING THEIR BIOLOGICAL ROLES IN DISEASE EXPANSION, THE REGULATION OF LSCS AND TKI RESISTANCE. WE DECIDED TO SEPARATE THOSE PPS THAT HAVE BEEN VALIDATED IN PRIMARY CELL MODELS OR LEUKEMIA MOUSE MODELS FROM THOSE WHOSE STUDIES HAVE BEEN PERFORMED ONLY IN CELL LINES (AND, THUS, REQUIRE VALIDATION), AS THERE MAY BE DIFFERENCES IN THE MANNER THAT THE ASSOCIATED PATHWAYS ARE MODIFIED UNDER THESE TWO CONDITIONS. THIS REVIEW SUMMARIZES THE ROLES OF DIVERSE PPS, WITH HOPE THAT BETTER KNOWLEDGE OF THE INTERPLAY AMONG PHOSPHATASES AND KINASES WILL EVENTUALLY RESULT IN A BETTER UNDERSTANDING OF THIS DISEASE AND CONTRIBUTE TO ITS ERADICATION. 2021 11 3900 29 LATEST INSIGHTS INTO PATHOGENESIS OF MYCOSIS FUNGOIDES AND CUTANEOUS T-CELL LYMPHOMA. CUTANEOUS T-CELL LYMPHOMA (CTCL) IS A RARE BUT INCREASING MALIGNANCY WHOSE PROTEAN MANIFESTATIONS NECESSARILY PRESENT IN THE INTEGUMENT, BUT CAN ALSO SPREAD TO INVOLVE BLOOD, LYMPH NODES AND INTERNAL ORGANS. WE HAVE DEVELOPED EFFICACIOUS AND VARIED THERAPIES TO TREAT EARLY AND ADVANCED STAGE DISEASE, BUT THERE ARE STILL MANY WHO SUFFER TREMENDOUSLY FROM THIS ILLNESS. ALTHOUGH THE PATHOGENESIS OF THIS CANCER REMAINS FRUSTRATINGLY ELUSIVE, OVER THE LAST 200 YEARS WE HAVE GENERATED A ROBUST BODY OF EVIDENCE THAT POINTS TOWARD POSSIBLE SINGULAR AS WELL AS MULTIFACTORIAL ETIOLOGIES. COMBINING THE HISTORICAL HYPOTHESES WHICH HAVE FOCUSED UPON THE CONCEPT OF INFECTIOUS CAUSES, INCLUDING CARCINOGENIC GENOMIC VIRAL INTEGRATION AND BACTERIAL SUPERANTIGENIC CHRONIC STIMULATION AS WELL AS INDUSTRIAL/OCCUPATIONAL EXPOSURE, ALONG WITH THE MORE RECENT REVELATIONS OF BOTH GENETIC AND EPIGENETIC ALTERATION AND IMMUNE DYSREGULATION, WE ARE CLOSER THAN EVER TO UNDERSTANDING THE ETIOLOGY OF CTCL. IT IS THROUGH THIS KNOWLEDGE AND CONTINUED RESEARCH EFFORTS THAT WE WILL BE ABLE TO BETTER DIAGNOSE, TREAT, AND POTENTIALLY PREVENT OR CURE CTCL. 2017 12 5785 23 SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 RAT LIVER EPITHELIAL CELLS. SEVERAL STUDIES HAVE SHOWN THAT CULTURED RAT LIVER EPITHELIAL CELLS TRANSFORM SPONTANEOUSLY AFTER CHRONIC MAINTENANCE IN A CONFLUENT STATE IN VITRO. IN THE PRESENT STUDY, MULTIPLE INDEPENDENT LINEAGES OF LOW-PASSAGE WB-F344 RAT LIVER EPITHELIAL STEM-LIKE CELLS WERE INITIATED AND SUBJECTED IN PARALLEL TO SELECTION FOR SPONTANEOUS TRANSFORMATION TO DETERMINE WHETHER SPONTANEOUS ACQUISITION OF TUMORIGENICITY WAS THE RESULT OF EVENTS (GENETIC OR EPIGENETIC) THAT OCCURRED INDEPENDENTLY AND STOCHASTICALLY, OR REFLECTED THE EXPRESSION OF A PRE-EXISTING ALTERATION WITHIN THE PARENTAL WB-F344 CELL LINE. TEMPORAL ANALYSIS OF THE SPONTANEOUS ACQUISITION OF TUMORIGENICITY BY WB-F344 CELLS DEMONSTRATED LINEAGE-SPECIFIC DIFFERENCES IN THE TIME OF FIRST EXPRESSION OF THE TUMORIGENIC PHENOTYPE, FREQUENCIES AND LATENCIES OF TUMOR FORMATION, AND TUMOR DIFFERENTIATIONS. ALTHOUGH SPONTANEOUSLY TRANSFORMED WB-F344 CELLS PRODUCED DIVERSE TUMOR TYPES (INCLUDING HEPATOCELLULAR CARCINOMAS, CHOLANGIOCARCINOMAS, HEPATOBLASTOMAS, AND OSTEOGENIC SARCOMAS), INDIVIDUAL LINEAGES YIELDED TUMORS WITH CONSISTENT AND SPECIFIC PATTERNS OF DIFFERENTIATION. THESE RESULTS PROVIDE SUBSTANTIAL EVIDENCE THAT THE STOCHASTIC ACCUMULATION OF INDEPENDENT TRANSFORMING EVENTS DURING THE SELECTION REGIMEN IN VITRO WERE RESPONSIBLE FOR SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 CELLS. FURTHERMORE, CELL LINEAGE COMMITMENT TO A SPECIFIC DIFFERENTIATION PROGRAM WAS STABLE WITH TIME IN CULTURE AND WITH SITE OF TRANSPLANTATION. THIS IS THE FIRST REPORT OF A COHORT OF RELATED, BUT INDEPENDENT, RAT LIVER EPITHELIAL CELL LINES THAT COLLECTIVELY PRODUCE A SPECTRUM OF TUMOR TYPES BUT INDIVIDUALLY REPRODUCE A SPECIFIC TUMOR TYPE. THESE CELL LINES WILL PROVIDE VALUABLE REAGENTS FOR INVESTIGATION OF THE MOLECULAR MECHANISMS INVOLVED IN THE DIFFERENTIATION OF HEPATIC STEM-LIKE CELLS AND FOR EXAMINATION OF POTENTIAL CAUSAL RELATIONSHIPS IN SPONTANEOUSLY TRANSFORMED RAT LIVER EPITHELIAL CELL LINES BETWEEN MOLECULAR/CELLULAR ALTERATIONS AND THE ABILITY TO PRODUCE TUMORS IN SYNGENEIC ANIMALS. 1998 13 628 26 BIOLOGICAL AND CLINICAL INSIGHT FROM ANALYSIS OF THE TUMOR B-CELL RECEPTOR STRUCTURE AND FUNCTION IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE B-CELL RECEPTOR (BCR) IS ESSENTIAL TO THE BEHAVIOR OF THE MAJORITY OF NORMAL AND NEOPLASTIC MATURE B CELLS. THE IDENTIFICATION IN 1999 OF THE TWO MAJOR CLL SUBSETS EXPRESSING UNMUTATED IMMUNOGLOBULIN (IG) VARIABLE REGION GENES (U-IGHV, U-CLL) OF PRE-GERMINAL CENTER ORIGIN AND POOR PROGNOSIS, AND MUTATED IGHV (M-CLL) OF POST-GERMINAL CENTER ORIGIN AND GOOD PROGNOSIS, IGNITED INTENSIVE INVESTIGATIONS ON STRUCTURE AND FUNCTION OF THE TUMOR BCR. THESE INVESTIGATIONS HAVE PROVIDED FUNDAMENTAL INSIGHT INTO CLL BIOLOGY AND EVENTUALLY THE MECHANISTIC RATIONALE FOR THE DEVELOPMENT OF SUCCESSFUL THERAPIES TARGETING BCR SIGNALING. U-CLL AND M-CLL ARE CHARACTERIZED BY VARIABLE LOW SURFACE IGM (SIGM) EXPRESSION AND SIGNALING CAPACITY. VARIABILITY OF SIGM CAN IN PART BE EXPLAINED BY CHRONIC ENGAGEMENT WITH (AUTO)ANTIGEN AT TISSUE SITES. HOWEVER, OTHER ENVIRONMENTAL ELEMENTS, GENETIC CHANGES, AND EPIGENETIC SIGNATURES ALSO CONTRIBUTE TO THE SIGM VARIABILITY. THE VARIABLE LEVELS HAVE CONSEQUENCES ON THE BEHAVIOR OF CLL, WHICH IS IN A STATE OF ANERGY WITH AN INDOLENT CLINICAL COURSE WHEN SIGM EXPRESSION IS LOW, OR PUSHED TOWARDS PROLIFERATION AND A MORE AGGRESSIVE CLINICAL COURSE WHEN SIGM EXPRESSION IS HIGH. EFFICACY OF THERAPIES THAT TARGET BTK MAY ALSO BE AFFECTED BY THE VARIABLE SIGM LEVELS AND SIGNALING AND, IN PART, EXPLAIN THE DEVELOPMENT OF RESISTANCE. 2022 14 2025 22 EPIGENETIC CHANGES DURING DISEASE PROGRESSION IN A MURINE MODEL OF HUMAN CHRONIC LYMPHOCYTIC LEUKEMIA. EPIGENETIC ALTERATIONS, INCLUDING GAIN OR LOSS OF DNA METHYLATION, ARE A HALLMARK OF NEARLY EVERY MALIGNANCY. CHANGES IN DNA METHYLATION CAN IMPACT EXPRESSION OF CANCER-RELATED GENES INCLUDING APOPTOSIS REGULATORS AND TUMOR SUPPRESSORS. BECAUSE SUCH EPIGENETIC CHANGES ARE REVERSIBLE, THEY ARE BEING AGGRESSIVELY INVESTIGATED AS POTENTIAL THERAPEUTIC TARGETS. HERE WE USE THE EMU-TCL1 TRANSGENIC MOUSE MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TO DETERMINE THE TIMING AND PATTERNS OF ABERRANT DNA METHYLATION, AND TO INVESTIGATE THE MECHANISMS THAT LEAD TO ABERRANT DNA METHYLATION. WE SHOW THAT CLL CELLS FROM EMU-TCL1 MICE AT VARIOUS STAGES RECAPITULATE EPIGENETIC ALTERATIONS SEEN IN HUMAN CLL. ABERRANT METHYLATION OF PROMOTER SEQUENCES IS OBSERVED AS EARLY AS 3 MONTHS OF AGE IN THESE ANIMALS, WELL BEFORE DISEASE ONSET. ABNORMALLY METHYLATED PROMOTER REGIONS INCLUDE BINDING SITES FOR THE TRANSCRIPTION FACTOR FOXD3. WE SHOW THAT LOSS OF FOXD3 EXPRESSION DUE TO AN NF-KAPPAB P50/P50:HDAC1 REPRESSOR COMPLEX OCCURS IN TCL1-POSITIVE B CELLS BEFORE METHYLATION. THEREFORE, SPECIFIC TRANSCRIPTIONAL REPRESSION IS AN EARLY EVENT LEADING TO EPIGENETIC SILENCING OF TARGET GENES IN MURINE AND HUMAN CLL. THESE RESULTS PROVIDE STRONG RATIONALE FOR THE DEVELOPMENT OF STRATEGIES TO TARGET NF-KAPPAB COMPONENTS IN CLL AND POTENTIALLY OTHER B-CELL MALIGNANCIES. 2009 15 4549 24 MUTATION ANALYSIS OF THERAPY-RELATED MYELOID NEOPLASMS. WE ANALYZED THE GENETIC MUTATION STATUS OF 13 PATIENTS WITH THERAPY-RELATED MYELOID NEOPLASMS (T-MN). CONSISTENT WITH PREVIOUS REPORTS, T-MN CELLS PREFERENTIALLY ACQUIRED MUTATIONS IN TP53 AND EPIGENETIC MODIFYING GENES, INSTEAD OF MUTATIONS IN TYROSINE KINASE AND SPLICEOSOME GENES. FURTHERMORE, WE COMPARED THE MUTATION STATUS OF THREE T-MN CELLS WITH EACH OF THE INITIAL LYMPHOID MALIGNANT CELLS, AND IDENTIFIED COMMON MUTATIONS AMONG T-MN AND THE INITIAL MALIGNANT CELLS IN TWO PATIENTS. IN A PATIENT WHO DEVELOPED CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AFTER FOLLICULAR LYMPHOMA (FL), TET2 MUTATION WAS IDENTIFIED IN BOTH CMML AND FL CELLS. NOTABLY, THE TET2 MUTATION WAS ALSO IDENTIFIED IN PERIPHERAL BLOOD CELLS IN THE DISEASE-FREE PERIOD WITH THE SAME ALLELIC FREQUENCY AS CMML AND FL CELLS, BUT NOT IN A GERM-LINE CONTROL, INDICATING THAT THE TET2 MUTATION OCCURRED SOMATICALLY IN THE INITIATING CLONE FOR BOTH MALIGNANT CELLS. ON THE OTHER HAND, A GERM-LINE MYB MUTATION WAS IDENTIFIED IN A PATIENT WHO DEVELOPED MYELODYSPLASTIC SYNDROMES (MDS) AFTER FL. THESE RESULTS SUGGEST THAT GERM-LINE DEPOSITION AND CLONAL HEMATOPOIESIS ARE CLOSELY ASSOCIATED WITH T-MN SUSCEPTIBILITY; HOWEVER, FURTHER ANALYSIS IS NECESSARY TO CLARIFY THE MECHANISM REQUIRED TO PROVIDE THE INITIATING CLONE WITH LINEAGE COMMITMENT AND CLONAL EXPANSION. 2018 16 6468 22 TISSUE-SPECIFIC ENRICHMENT OF LYMPHOMA RISK LOCI IN REGULATORY ELEMENTS. THOUGH NUMEROUS POLYMORPHISMS HAVE BEEN ASSOCIATED WITH RISK OF DEVELOPING LYMPHOMA, HOW THESE VARIANTS FUNCTION TO PROMOTE TUMORIGENESIS IS POORLY UNDERSTOOD. HERE, WE REPORT THAT LYMPHOMA RISK SNPS, ESPECIALLY IN THE NON-HODGKIN'S LYMPHOMA SUBTYPE CHRONIC LYMPHOCYTIC LEUKEMIA, ARE SIGNIFICANTLY ENRICHED FOR CO-LOCALIZATION WITH EPIGENETIC MARKS OF ACTIVE GENE REGULATION. THESE ENRICHMENTS WERE SEEN IN A LYMPHOID-SPECIFIC MANNER FOR NUMEROUS ENCODE DATASETS, INCLUDING DNASE-HYPERSENSITIVITY AS WELL AS MULTIPLE SEGMENTATION-DEFINED ENHANCER REGIONS. FURTHERMORE, WE IDENTIFY PUTATIVELY FUNCTIONAL SNPS THAT ARE BOTH IN REGULATORY ELEMENTS IN LYMPHOCYTES AND ARE ASSOCIATED WITH GENE EXPRESSION CHANGES IN BLOOD. WE DEVELOPED AN ALGORITHM, UES, THAT USES A MONTE CARLO SIMULATION APPROACH TO CALCULATE THE ENRICHMENT OF PREVIOUSLY IDENTIFIED RISK SNPS IN VARIOUS FUNCTIONAL ELEMENTS. THIS MULTISCALE APPROACH INTEGRATING MULTIPLE DATASETS HELPS DISENTANGLE THE UNDERLYING BIOLOGY OF LYMPHOMA, AND MORE BROADLY, IS GENERALLY APPLICABLE TO GWAS RESULTS FROM OTHER DISEASES AS WELL. 2015 17 3091 20 GENOMIC AND EPIGENOMIC HETEROGENEITY IN CHRONIC LYMPHOCYTIC LEUKEMIA. DEFINING FEATURES OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ARE NOT ONLY ITS IMMUNOPHENOTYPE OF CD19(+)CD5(+)CD23(+)SIGDIM EXPRESSING CLONAL MATURE B CELLS BUT ALSO ITS HIGHLY VARIABLE CLINICAL COURSE. IN RECENT YEARS, ADVANCES IN MASSIVELY PARALLEL SEQUENCING TECHNOLOGIES HAVE LED TO RAPID PROGRESS IN OUR UNDERSTANDING OF THE CLL GENOME AND EPIGENOME. OVERALL, THESE STUDIES HAVE CLEARLY DEMARCATED NOT ONLY THE VAST DEGREE OF GENETIC AND EPIGENETIC HETEROGENEITY AMONG INDIVIDUALS WITH CLL BUT ALSO EVEN WITHIN INDIVIDUAL PATIENT LEUKEMIAS. WE HEREIN REVIEW THE RAPIDLY GROWING SERIES OF STUDIES ASSESSING THE GENETIC AND EPIGENETIC FEATURES OF CLL WITHIN CLINICALLY DEFINED PERIODS OF ITS GROWTH. THESE STUDIES STRONGLY SUGGEST AN EVOLVING SPECTRUM OF LESIONS OVER TIME AND THAT THESE FEATURES MAY HAVE CLINICAL IMPACT. 2015 18 2461 24 EPIGENETIC THERAPY AS A PUTATIVE MOLECULAR TARGET TO MODULATE B CELL BIOLOGY AND BEHAVIOR IN THE CONTEXT OF IMMUNOLOGICAL DISORDERS. HISTONE DEACETYLASE- (HDAC-) DEPENDENT EPIGENETIC MECHANISMS HAVE BEEN WIDELY EXPLORED IN THE LAST DECADE IN DIFFERENT TYPES OF MALIGNANCIES IN PRECLINICAL STUDIES. THIS EFFORT LED TO THE DISCOVERY AND DEVELOPMENT OF A RANGE OF NEW HDAC INHIBITORS (IHDAC) WITH DIFFERENT CHEMICAL PROPERTIES AND SELECTIVE ABILITIES. IN FACT, HEMATOLOGICAL MALIGNANCIES WERE THE FIRST ONES TO HAVE NEW IHDACS APPROVED FOR CLINICAL USE, SUCH AS VORINOSTAT AND ROMIDEPSIN FOR CUTANEOUS T CELL LYMPHOMA AND PANOBINOSTAT FOR MULTIPLE MYELOMA. BESIDES THESE PROMISING ALREADY APPROVED IHDACS, WE HIGHLIGHT A RANGE OF STUDIES FOCUSING ON THE HDAC-DEPENDENT EPIGENETIC CONTROL OF B CELL DEVELOPMENT, BEHAVIOR, AND/OR FUNCTION. HERE, WE HIGHLIGHT 21 IHDACS WHICH HAVE BEEN STUDIED IN THE LITERATURE IN THE CONTEXT OF B CELL DEVELOPMENT AND/OR DYSFUNCTION MOSTLY FOCUSED ON B CELL LYMPHOMAGENESIS. REGARDLESS, WE HAVE IDENTIFIED 55 CLINICAL TRIALS USING 6 OUT OF 21 IHDACS TO APPROACH THEIR PUTATIVE ROLES ON B CELL MALIGNANCIES; NONE OF THEM FOCUSES ON PERITONEAL B CELL POPULATIONS. SINCE CELLS BELONGING TO THIS PECULIAR BODY COMPARTMENT, NAMED B1 CELLS, MAY CONTRIBUTE TO THE DEVELOPMENT OF AUTOIMMUNE PATHOLOGIES, SUCH AS LUPUS, A BETTER UNDERSTANDING OF THE HDAC-DEPENDENT EPIGENETIC MECHANISMS THAT CONTROL ITS BIOLOGY AND BEHAVIOR MIGHT SHED LIGHT ON IHDAC USE TO MANAGE THESE IMMUNOLOGICAL DYSFUNCTIONS. IN THIS SENSE, IHDACS MIGHT EMERGE AS A PROMISING NEW APPROACH FOR TRANSLATIONAL STUDIES IN THIS FIELD. IN THIS REVIEW, WE DISCUSS A PUTATIVE ROLE OF IHDACS IN THE MODULATION OF PERITONEAL B CELL SUBPOPULATION'S BALANCE AS WELL AS THEIR ROLE AS THERAPEUTIC AGENTS IN THE CONTEXT OF CHRONIC DISEASES MEDIATED BY PERITONEAL B CELLS. 2020 19 5989 27 TGF-BETA/SMAD PATHWAY IS MODULATED BY MIR-26B-5P: ANOTHER PIECE IN THE PUZZLE OF CHRONIC LYMPHOCYTIC LEUKEMIA PROGRESSION. CLINICAL AND MOLECULAR HETEROGENEITY ARE HALLMARKS OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), A NEOPLASM CHARACTERIZED BY ACCUMULATION OF MATURE AND CLONAL LONG-LIVED CD5 + B-LYMPHOCYTES. MUTATIONAL STATUS OF THE IGHV GENE OF LEUKEMIC CLONES IS A POWERFUL PROGNOSTIC TOOL IN CLL, AND IT IS WELL ESTABLISHED THAT UNMUTATED CLLS (U-CLLS) HAVE WORSE EVOLUTION THAN MUTATED CASES. NEVERTHELESS, PROGRESSION AND TREATMENT REQUIREMENT OF PATIENTS CAN EVOLVE INDEPENDENTLY FROM THE MUTATIONAL STATUS. MICROENVIRONMENT SIGNALING OR EPIGENETIC CHANGES PARTIALLY EXPLAIN THIS DIFFERENT BEHAVIOR. THUS, WE THINK THAT DETAILED CHARACTERIZATION OF THE MIRNAS LANDSCAPE FROM PATIENTS WITH DIFFERENT CLINICAL EVOLUTION COULD FACILITATE THE UNDERSTANDING OF THIS HETEROGENEITY. SINCE MIRNAS ARE KEY PLAYERS IN LEUKEMIA PATHOGENESIS AND EVOLUTION, WE AIM TO BETTER CHARACTERIZE DIFFERENT CLL BEHAVIORS BY COMPARING THE MIRNOME OF CLINICALLY PROGRESSIVE U-CLLS VS. STABLE U-CLLS. OUR DATA SHOW UP-REGULATION OF MIR-26B-5P, MIR-106B-5P, AND MIR-142-5P IN PROGRESSIVE CASES AND INDICATE A KEY ROLE FOR MIR-26B-5P DURING CLL PROGRESSION. SPECIFICALLY, UP-REGULATION OF MIR-26B-5P IN CLL CELLS BLOCKS TGF-BETA/SMAD PATHWAY BY DOWN-MODULATION OF SMAD-4, RESULTING IN LOWER EXPRESSION OF P21(-CIP1) KINASE INHIBITOR AND HIGHER EXPRESSION OF C-MYC ONCOGENE. THIS WORK DESCRIBES A NEW MOLECULAR MECHANISM LINKING CLL PROGRESSION WITH TGF-BETA MODULATION AND PROPOSES AN ALTERNATIVE STRATEGY TO EXPLORE IN CLL THERAPY. 2022 20 5691 27 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