1 2979 80 GENETIC BACKGROUND OF JUVENILE IDIOPATHIC ARTHRITIS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS THE MOST COMMON CHRONIC RHEUMATOLOGIC DISEASE IN CHILDREN. JIA IS A GROUP OF DISORDERS THAT SHARE THE CLINICAL MANIFESTATION OF CHRONIC JOINT INFLAMMATION. THE HUMAN LEUKOCYTE ANTIGEN REGION (HLA) SEEMS TO BE A MAJOR SUSCEPTIBILITY LOCUS FOR JIA THAT IS ESTIMATED TO ACCOUNT FOR 17% OF FAMILIAL SEGREGATION OF THE DISEASE. TO DATE, AROUND 20 NON-HLA LOCI CONFERRING SUSCEPTIBILITY TO JIA WERE FOUND. AT LEAST A HALF OF THOSE ARE SHARED BETWEEN JIA AND RHEUMATOID ARTHRITIS (RA), AN ADULT RHEUMATIC DISEASE, THEREBY SUGGESTING FOR SIMILARITY OF PATHOGENIC MECHANISMS OF BOTH DISEASES. NEW FINDINGS ALSO SUGGEST FOR A LIKELY ROLE OF EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF JIA THAT SHOULD BE INVESTIGATED IN THE FUTURE. 2014 2 3507 27 IDENTIFICATION OF TARGET GENES AT JUVENILE IDIOPATHIC ARTHRITIS GWAS LOCI IN HUMAN NEUTROPHILS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS THE MOST COMMON CHRONIC RHEUMATIC DISEASE AMONG CHILDREN WHICH COULD CAUSE SEVERE DISABILITY. GENOMIC STUDIES HAVE DISCOVERED SUBSTANTIAL NUMBER OF RISK LOCI FOR JIA, HOWEVER, THE MECHANISM OF HOW THESE LOCI AFFECT JIA DEVELOPMENT IS NOT FULLY UNDERSTOOD. NEUTROPHIL IS AN IMPORTANT CELL TYPE INVOLVED IN AUTOIMMUNE DISEASES. TO BETTER UNDERSTAND THE BIOLOGICAL FUNCTION OF GENETIC LOCI IN NEUTROPHILS DURING JIA DEVELOPMENT, WE TOOK AN INTEGRATED MULTI-OMICS APPROACH TO IDENTIFY TARGET GENES AT JIA RISK LOCI IN NEUTROPHILS AND CONSTRUCTED A PROTEIN-PROTEIN INTERACTION NETWORK VIA A MACHINE LEARNING APPROACH. WE IDENTIFIED GENES LIKELY TO BE JIA RISK LOCI TARGETED GENES IN NEUTROPHILS WHICH COULD CONTRIBUTE TO JIA DEVELOPMENT. 2019 3 6787 73 [CONTRIBUTION OF NON-HLA GENES TO JUVENILE IDIOPATHIC ARTHRITIS SUSCEPTIBILITY]. JUVENILE IDIOPATHIC ARTHRITIS (JAL4) IS THE MOST COMMON CHRONIC RHEUMATOLOGIC DISEASE IN CHILDREN. JIA IS A GROUP OF DISORDERS THAT SHARE THE CLINICAL MANIFESTATION OF CHRONIC JOINT INFLAMMATION. THE HUMAN LEUKOCYTE ANTIGEN REGION (HLA) SEEMS TO BE A MAJOR SUSCEPTIBILITY LOCUS FOR JIA THAT IS ESTIMATED TO ACCOUNT FOR 17% OF FAMILIAL SEGREGATION OF THE DISEASE. GENOME-WIDE ASSOCIATION STUDIES (GWAS), CASE-CONTROL STUDIES AND META-ANALYSES OF THE POST-GWAS ERA REVEALED OVER 20 NON-HLA LOCI CONFERRING SUSCEPTIBILITY TO JIA. AT LEAST A HALF OF THOSE ARE SHARED BETWEEN JIA AND RHEUMATOID ARTHRITIS, AN ADULT RHEUMATIC DISEASE, THEREBY SUGGESTING FOR SIMILARITY OF PATHOGENIC MECHANISMS OF BOTH DISEASES. NEW FINDINGS ALSO SUGGEST FOR A LIKELY ROLE OF EPIGENETIC ALTERATIONS IN THE PATHOGENESIS OF JIA THAT SHOULD BE INVESTIGATED IN THE FUTURE. 2014 4 3871 14 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 5 4656 27 NEW ADVANCES IN JUVENILE IDIOPATHIC ARTHRITIS. JUVENILE IDIOPATHIC ARTHRITIS (JIA) COMPRISES A GROUP OF HETEROGENEOUS DISORDERS OF CHRONIC ARTHRITIS IN CHILDHOOD WITH NO APPARENT ETIOLOGY. JUVENILE IDIOPATHIC ARTHRITIS IS THE MOST COMMON PEDIATRIC RHEUMATIC DISEASE AND IS ASSOCIATED WITH SIGNIFICANT LONG-TERM MORBIDITY AND MORTALITY. THERE HAVE BEEN MAJOR ADVANCES IN RECENT YEARS IN OUR UNDERSTANDING OF THE PATHOGENESIS OF JIA, THE DEFINITION OF DISEASE CONTROL, AND BIOLOGICAL TREATMENTS FOR JIA. MULTIPLE ENVIRONMENTAL AND GENETIC FACTORS HAVE BEEN LINKED WITH THE ONSET AND / OR THE EXACERBATION OF JIA, INCLUDING PERINATAL FACTORS, VIRAL AND BACTERIAL INFECTIONS, EPIGENETIC FACTORS, AND MALNUTRITION. HOWEVER, NO SINGLE CAUSATIVE FACTOR HAS BEEN IDENTIFIED TO DATE. AS OUR UNDERSTANDING OF THE COMPLEX NETWORK OF IMMUNE CELLS AND INFLAMMATORY CYTOKINES HAS IMPROVED, BIOLOGICS HAVE BEEN DEVELOPED TO MODULATE THE INFLAMMATORY PROCESSES. INDEED, A NUMBER OF SUCH BIOLOGICS HAVE BEEN DEMONSTRATED EFFECTIVE FOR THE TREATMENT OF JIA. ALTHOUGH BIOLOGIC AGENTS MAY ALLEVIATE THE INFLAMMATION ASSOCIATED WITH JIA AND PREVENT DISABILITY CAUSED BY JOINT DESTRUCTION, CONTINUED AND COMPREHENSIVE OBSERVATION IS REQUIRED TO DETERMINE THE LONG-TERM OUTCOMES ASSOCIATED WITH SUCH TREATMENT. 2012 6 3872 26 JUVENILE MYELOMONOCYTIC LEUKEMIA-A COMPREHENSIVE REVIEW AND RECENT ADVANCES IN MANAGEMENT. JUVENILE MYELOMONOCYTIC LEUKEMIA (JMML) IS A RARE PEDIATRIC MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM OVERLAP DISEASE. JMML IS ASSOCIATED WITH MUTATIONS IN THE RAS PATHWAY GENES RESULTING IN THE MYELOID PROGENITORS BEING SENSITIVE TO GRANULOCYTE MONOCYTE COLONY-STIMULATING FACTOR (GM-CSF). KARYOTYPE ABNORMALITIES AND ADDITIONAL EPIGENETIC ALTERATIONS CAN ALSO BE FOUND IN JMML. NEUROFIBROMATOSIS AND NOONAN'S SYNDROME HAVE A PREDISPOSITION FOR JMML. IN A FEW PATIENTS, THE RAS GENES (NRAS, KRAS, AND PTPN11) ARE MUTATED AT THE GERMLINE AND THIS USUALLY RESULTS IN A TRANSIENT MYELOPROLIFERATIVE DISORDER WITH A GOOD PROGNOSIS. JMML WITH SOMATIC RAS MUTATION BEHAVES AGGRESSIVELY. JMML PRESENTS WITH CYTOPENIAS AND LEUKEMIC INFILTRATION INTO ORGANS. THE LABORATORY FINDINGS INCLUDE HYPERLEUKOCYTOSIS, MONOCYTOSIS, INCREASED HEMOGLOBIN-F LEVELS, AND CIRCULATING MYELOID PRECURSORS. THE BLAST CELLS IN THE PERIPHERAL BLOOD/BONE-MARROW ASPIRATE ARE LESS THAN 20% AND THE ABSENCE OF THE BCR-ABL TRANSLOCATION HELPS TO DIFFERENTIATE FROM CHRONIC MYELOID LEUKEMIA. JMML SHOULD BE DIFFERENTIATED FROM IMMUNODEFICIENCIES, VIRAL INFECTIONS, INTRAUTERINE INFECTIONS, HEMOPHAGOLYMPHOHISTIOCYTOSIS, OTHER MYELOPROLIFERATIVE DISORDERS, AND LEUKEMIAS. CHEMOTHERAPY IS EMPLOYED AS A BRIDGE TO HSCT, EXCEPT IN FEW WITH LESS AGGRESSIVE DISEASE, IN WHICH CHEMOTHERAPY ALONE CAN RESULT IN LONG TERM REMISSION. AZACITIDINE HAS SHOWN PROMISE AS A SINGLE AGENT TO STABILIZE THE DISEASE. THE PROGNOSIS OF JMML IS POOR WITH ABOUT 50% OF PATIENTS SURVIVING AFTER AN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT). ALLOGENEIC HSCT IS THE ONLY KNOWN CURE FOR JMML TO DATE. MYELOABLATIVE CONDITIONING IS MOST COMMONLY USED WITH GRAFT VERSUS HOST DISEASE (GVHD) PROPHYLAXIS TAILORED TO THE AGGRESSIVENESS OF THE DISEASE. RELAPSES ARE COMMON EVEN AFTER HSCT AND A SECOND HSCT CAN SALVAGE A THIRD OF THESE PATIENTS. NOVEL OPTIONS IN THE TREATMENT OF JMML E.G., HYPOMETHYLATING AGENTS, MEK INHIBITORS, JAK INHIBITORS, TYROSINE KINASE INHIBITORS, ETC. ARE BEING EXPLORED. 2021 7 5473 31 RESPONSES OF PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS TO METHOTREXATE: A GENOMIC OUTLOOK. INTRODUCTION: JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS A CHRONIC DISEASE CHARACTERIZED BY PERSISTENT JOINT INFLAMMATION. JIA IS THE MOST COMMON PEDIATRIC CHRONIC RHEUMATIC DISEASE AND NO CURATIVE THERAPY IS CURRENTLY AVAILABLE. METHOTREXATE (MTX) IS AN IMPORTANT TREATMENT FOR JIA EVEN THOUGH A HIGH INTER-INDIVIDUAL VARIABILITY IN RESPONSE IS OBSERVED IN PATIENTS. AMONG THE FACTORS OF THIS VARIABILITY, GENETICS AND EPIGENETICS MIGHT PLAY AN IMPORTANT ROLE. AREAS COVERED: THIS REVIEW SUMMARIZES THE RESULTS OF PHARMACOGENETIC AND PHARMACOEPIGENETIC STUDIES REGARDING MTX RESPONSE IN JIA. STUDIES CONSIDERING EPIGENETIC FACTORS IN JIA PATIENTS ARE STILL VERY LIMITED, THEREFORE THIS REVIEW INCLUDES ALSO STUDIES PERFORMED IN ADULT PATIENTS WITH RHEUMATOID ARTHRITIS. MOREOVER, THE RELEVANCE OF BIOMARKERS MEASURED IN BLOOD OR URINE OF JIA PATIENTS IN RELATION TO MTX TREATMENT IS DISCUSSED. EXPERT OPINION: NOWADAYS, EVEN THOUGH MANY PHARMACOGENOMICS STUDIES HAVE BEEN PUBLISHED, A SPECIFIC GENETIC MARKER PREDICTOR OF MTX EFFICACY OR ADVERSE EVENTS HAS NOT YET BEEN IDENTIFIED. ENCOURAGING RESULTS ARE AVAILABLE AND GREAT EXPECTATIONS RELY ON THE STUDY OF EPIGENETICS. FUTURE STUDIES ARE NEEDED IN ORDER TO IDENTIFY GENETIC AND EPIGENETIC BIOMARKERS THAT CAN BE IMPLEMENTED IN THE CLINICAL PRACTICE. 2021 8 4471 23 MOLECULAR PATHOGENESIS OF ATYPICAL CML, CMML AND MDS/MPN-UNCLASSIFIABLE. ACCORDING TO THE 2008 WHO CLASSIFICATION, THE CATEGORY OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) INCLUDES ATYPICAL CHRONIC MYELOID LEUKAEMIA (ACML), CHRONIC MYELOMONOCYTIC LEUKAEMIA (CMML), MDS/MPN-UNCLASSIFIABLE (MDS/MPN-U), JUVENILE MYELOMONOCYTIC LEUKAEMIA (JMML) AND A "PROVISIONAL" ENTITY, REFRACTORY ANAEMIA WITH RING SIDEROBLASTS AND THROMBOCYTOSIS (RARS-T). THE REMARKABLE PROGRESS IN OUR UNDERSTANDING OF THE SOMATIC PATHOGENESIS OF MDS/MPN HAS MADE IT CLEAR THAT THERE IS CONSIDERABLE OVERLAP AMONG THESE DISEASES AT THE MOLECULAR LEVEL, AS WELL AS LAYERS OF UNEXPECTED COMPLEXITY. DEREGULATION OF SIGNALLING PLAYS AN IMPORTANT ROLE IN MANY CASES, AND IS CLEARLY LINKED TO MORE HIGHLY PROLIFERATIVE DISEASE. OTHER MUTATIONS AFFECT A RANGE OF OTHER ESSENTIAL, INTERRELATED CELLULAR MECHANISMS, INCLUDING EPIGENETIC REGULATION, RNA SPLICING, TRANSCRIPTION, AND DNA DAMAGE RESPONSE. THE VARIOUS COMBINATIONS OF MUTATIONS INDICATE A MULTI-STEP PATHOGENESIS, WHICH LIKELY CONTRIBUTES TO THE MARKED CLINICAL HETEROGENEITY OF THESE DISORDERS. THE DELINEATION OF COMPLEX CLONAL ARCHITECTURES MAY SERVE AS THE CORNERSTONE FOR THE IDENTIFICATION OF NOVEL THERAPEUTIC TARGETS AND LEAD TO BETTER PATIENT OUTCOMES. THIS REVIEW SUMMARIZES SOME OF THE CURRENT KNOWLEDGE OF MOLECULAR PATHOGENETIC LESIONS IN THE MDS/MPN SUBTYPES THAT ARE SEEN IN ADULTS: ATYPICAL CML, CMML AND MDS/MPN-U. 2015 9 4562 16 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 10 5041 25 PHARMACOGENETICS: CAN GENES DETERMINE TREATMENT EFFICACY AND SAFETY IN JIA? JUVENILE IDIOPATHIC ARTHRITIS (JIA) IS THE MOST COMMON CHRONIC RHEUMATIC CONDITION IN CHILDHOOD, WITH MANY CHILDREN REQUIRING IMMUNOMODULATORY THERAPIES FOR MANY YEARS FOLLOWING DIAGNOSIS. A CONSIDERABLE PROPORTION OF CHILDREN EXPERIENCE THERAPEUTIC INEFFICACY OR SUBSTANTIAL ADVERSE EFFECTS, OR BOTH, BUT A LACK OF RELIABLE CLINICAL INDICATORS AND BIOMARKERS TO PREDICT TREATMENT RESPONSE PREVENTS OPTIMIZATION OF EXISTING THERAPIES. THE IDENTIFICATION OF VALID CANDIDATE GENE VARIANTS INVOLVED IN THE PATHWAYS OF METHOTREXATE AND ETANERCEPT, THE MOST COMMONLY USED MEDICATIONS IN JIA, HAS SEEN LITTLE SUCCESS TO DATE. THE LIMITED SUCCESS OF THESE STUDIES IS POSSIBLY DUE TO THE PRESENCE OF CONFOUNDING VARIABLES IN THE STUDY POPULATIONS, THE HETEROGENEITY OF OUTCOME PARAMETERS USED TO DETERMINE TREATMENT RESPONSE AND THE SMALL NUMBER OF CANDIDATE GENE VARIANTS ANALYSED. THE FIRST GENOME-WIDE PHARMACOGENETIC STUDY IN JIA HAS IDENTIFIED GENE REGIONS OF PARTICULAR BIOLOGICAL INTEREST, BUT THESE FINDINGS REQUIRE VALIDATION. MOREOVER, EPIGENETIC MECHANISMS AS WELL AS ONTOGENY PROCESSES MIGHT BE ADDITIONAL FACTORS INFLUENCING DRUG RESPONSES. ACCESS TO LARGE, WELL-DOCUMENTED JIA COHORTS AND THE RAPID DEVELOPMENT OF ADVANCED GENOME ANALYTICS IS USHERING IN A PERSONALIZED APPROACH TO TREATMENT. THE DISCOVERY OF NEW PHARMACOGENOMIC BIOMARKERS AND SYSTEMS PATHWAYS CAN PROVIDE NEW DRUG TARGETS AND PREDICTIVE TOOLS FOR IMPROVED DRUG RESPONSE AND FEWER ADVERSE DRUG REACTIONS IN JIA. 2014 11 4442 17 MOLECULAR GENETICS OF MDS/MPN OVERLAP SYNDROMES. THE MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE A HETEROGENOUS GROUP OF MYELOID MALIGNANCIES HALLMARKED BY CLINICOPATHOLOGIC FEATURES THAT OVERLAP WITH MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE NEOPLASMS. FORMALLY RECOGNIZED BY THE WORLD HEALTH ORGANIZATION, THIS GROUP INCLUDES THE ENTITIES CHRONIC MYELOMONOCYTIC LEUKEMIA, JUVENILE MYELOMONOCYTIC LEUKEMIA, ATYPICAL CHRONIC MYELOID LEUKEMIA, MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS AND MDS/MPN, UNCLASSIFIABLE. ADVANCEMENTS IN NEXT GENERATION SEQUENCING HAVE BEGUN TO UNRAVEL THE MOLECULAR UNDERPINNINGS OF THESE DISEASES, IDENTIFYING AN ARRAY OF RECURRENTLY MUTATED GENES INVOLVED IN EPIGENETIC REGULATION, RNA SPLICING, TRANSCRIPTION, AND CELL SIGNALING. DESPITE MOLECULAR OVERLAP WITH OTHER MYELOID MALIGNANCIES, EACH ENTITY DISPLAYS A UNIQUE SPECTRUM OF SOMATIC MUTATIONS SUPPORTING THEIR UNIQUE PATHOBIOLOGY AND CLINICAL FEATURES. IMPORTANTLY, MOLECULAR PROFILING IS BECOMING AN INTEGRAL TOOL UTILIZED IN ROUTINE CLINICAL PRACTICE. THIS REVIEW SUMMARIZES OUR CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF OVERLAP SYNDROMES AND DETAILS THE IMPACT OF SOMATIC MUTATIONS IN DIAGNOSTIC, PROGNOSTIC, AND THERAPEUTIC DECISION-MAKING. 2020 12 4988 23 PATTERNS OF HEMATOPOIETIC LINEAGE INVOLVEMENT IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 AND MALIGNANT MYELOID DISORDERS. CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 (NF1) ARE AT INCREASED RISK OF DEVELOPING MALIGNANT MYELOID DISORDERS, PARTICULARLY JUVENILE CHRONIC MYELOGENOUS LEUKEMIA/JUVENILE MYELOMONOCYTIC LEUKEMIA (JCML/JMML). WE INVESTIGATED BONE MARROWS FROM 11 SUCH PATIENTS (8 BOYS AND 3 GIRLS) AND DETECTED ALLELIC LOSSES AT THE NF1 LOCUS IN 4 OF THEM AND PROBABLE LOSSES IN 2 OTHERS. TO DETERMINE WHICH HEMATOPOIETIC CELL LINEAGES WERE DERIVED FROM THE ABNORMAL CLONES, EPSTEIN-BARR VIRUS (EBV)-TRANSFORMED CELL LINES AND CD34+ CELLS WERE ANALYZED FROM 3 CHILDREN WITH JCML WITH ALLELIC LOSSES IN UNFRACTIONATED MARROW. CD34 CELLS FROM THESE 3 PATIENTS LACKED THE NORMAL NF1 ALLELE, WHEREAS EBV CELL LINES RETAINED IT. ERYTHROBLASTS PLUCKED FROM THE BURST-FORMING UNIT-ERYTHROID COLONIES OF ONE OF THESE CHILDREN LACKED THE NORMAL NF1 ALLELE. WE ALSO STUDIED A 10-MONTH-OLD BOY WITH NF1 WHO DEVELOPED AN UNUSUAL MYELOPROLIFERATIVE SYNDROME. HIS BONE MARROW AND EBV CELL LINE BOTH SHOWED LOSS OF THE NORMAL NF1 ALLELE. IN OUR SERIES AND IN THE LITERATURE, MALE SEX AND MATERNAL TRANSMISSION OF NF1 WERE ASSOCIATED WITH THE HIGHEST RISK OF MYELOID LEUKEMIA. THESE DATA (1) PROVIDE STRONG GENETIC EVIDENCE THAT NF1 FUNCTIONS AS A TUMOR-SUPPRESSOR IN EARLY MYELOPOIESIS, (2) CONFIRM THE CLONAL NATURE OF JCML/JMML, (3) SUGGEST THAT THE ELEVATION IN FETAL HEMOGLOBIN SEEN IN JCML/JMML IS A RESULT OF PRIMARY INVOLVEMENT OF ERYTHROID PROGENITORS IN THE MALIGNANT CLONE, (4) SHOW CONSISTENT LOSS OF NF1 IN THE CD34 CELLS OF AFFECTED CHILDREN AND SHOW THAT THE MALIGNANT CLONE MAY ALSO GIVE RISE TO PRE-B CELLS IN SOME CASES, AND (5) IMPLICATE EPIGENETIC FACTORS IN THE DEVELOPMENT OF LEUKEMIA IN CHILDREN WITH NF1. 1996 13 2956 15 GENETIC AND EPIGENETIC FACTORS INTERACTING WITH CLONAL HEMATOPOIESIS RESULTING IN CHRONIC MYELOMONOCYTIC LEUKEMIA. PURPOSE OF REVIEW: SINCE 2016, THE WHO HAS RECOGNIZED THE SIGNIFICANT PHENOTYPIC HETEROGENEITY OF CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AS A MYELODYSPLASTIC SYNDROME/MYELOPROLIFERATIVE NEOPLASM (MDS/MPN) OVERLAP DISEASE. ALTHOUGH SHARING MANY SOMATIC MUTATIONS WITH MDS AND MPN, THE PURPOSE OF THIS REVIEW IS TO PUT RECENT BIOLOGICAL FINDINGS OF CMML IN THE CONTEXT OF EVOLUTIONARY THEORY, HIGHLIGHTING IT AS A DISTINCT EVOLUTIONARY TRAJECTORY OCCURRING IN THE CONTEXT OF CLONAL HEMATOPOIESIS. RECENT FINDINGS: CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP), WITH A MUTATIONAL SPECTRUM AND PREVALENCE CORRELATED WITH AGE, HAS BEEN DEFINED. ENRICHED IN DNMT3A, TET2, AND ASXL1 MUTATIONS, CLONAL EVOLUTION CAN PROGRESS INTO VARIOUS EVOLUTIONARY TRAJECTORIES INCLUDING CMML. IMPACT OF FOUNDER MUTATIONS (PRIMARILY TET2) ON INCREASED HEMATOPOIETIC STEM CELL FITNESS HAS BEEN WELL CHARACTERIZED. EPISTATIC INTERACTIONS BETWEEN MUTATIONS AND EPIGENETIC EVENTS HAVE BEEN EXPLORED, BOTH IN CMML AND ITS PEDIATRIC COUNTERPART JUVENILE MYELOMONOCYTIC LEUKEMIA, INCLUDING CMML TRANSFORMATION TO ACUTE MYELOID LEUKEMIA. TOGETHER, THESE FINDINGS HAVE CONTRIBUTED SIGNIFICANTLY TOWARD CMML EVOLUTIONARY DYNAMICS. SUMMARY: DESPITE RELATIVELY FEW 'DRIVER' MUTATIONS IN CMML, EVOLUTIONARY DEVELOPMENT OF CHRONIC LEUKEMIA REMAINS INCOMPLETELY UNDERSTOOD. RECENT STUDIES HAVE SHED LIGHT ON THE IMPORTANCE OF STUDYING EPIGENETIC CONSEQUENCES OF MUTATIONS AND EPISTASIS BETWEEN KEY MUTATIONS TO BETTER UNDERSTAND CLONAL ARCHITECTURE AND EVOLUTIONARY DYNAMICS. 2020 14 986 24 CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) AND JUVENILE SPONDYLOARTHRITIS (JSPA): TO WHAT EXTENT ARE THEY RELATED? CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) IS AN AUTOINFLAMMATORY DISEASE OCCURRING MAINLY IN THE PEDIATRIC AGE GROUP (BEFORE 16 YEARS) AND GENERALLY PRESENTS AS A SEPARATE ENTITY. SYNOVITIS, ACNE, PUSTULOSIS, HYPEROSTOSIS AND OSTEITIS (SAPHO) SYNDROME COMBINES OSTEOARTICULAR AND CUTANEOUS INVOLVEMENT, SIMILAR TO CRMO, AND FALLS INTO THE SPECTRUM OF SPONDYLOARTHRITIS (SPA). THE FACT THAT A PATIENT CAN PROGRESS FROM ONE DISEASE TO ANOTHER RAISES THE QUESTION OF WHETHER CRMO, LIKE SAPHO, COULD FALL WITHIN THE SPECTRUM OF SPA, RANGING FROM A PREDOMINANTLY OSTEOARTICULAR FORM TO AN ENTHESITIC FORM WITH MORE OR LESS MARKED SKIN INVOLVEMENT. IN THIS REVIEW, WE SET OUT TO DISCUSS THIS HYPOTHESIS BY HIGHLIGHTING THE DIFFERENCES AND SIMILARITIES BETWEEN CRMO AND JUVENILE SPA IN CLINICAL, RADIOLOGICAL AND PATHOPHYSIOLOGICAL ASPECTS. A COMMON HYPOTHESIS COULD POTENTIALLY CONSIDER INTESTINAL DYSBIOSIS AS THE ORIGIN OF THESE DIFFERENT INFLAMMATORY DISEASES. INTERINDIVIDUAL FACTORS SUCH AS GENDER, ENVIRONMENT, GENETICS AND/OR EPIGENETIC BACKGROUND COULD ACT AS COMBINED DISEASE MODIFIERS. THIS IS WHY WE SUGGEST THAT PATHOPHYSIOLOGY, RATHER THAN CLINICAL PHENOTYPE, BE USED TO RECLASSIFY THESE DISEASES. 2023 15 4748 20 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 16 4491 26 MONOSOMY 7 MYELOPROLIFERATIVE DISEASE IN CHILDREN WITH NEUROFIBROMATOSIS, TYPE 1: EPIDEMIOLOGY AND MOLECULAR ANALYSIS. LOSS OF CONSTITUTIONAL HETEROZYGOSITY IS A COMMON MOLECULAR FEATURE OF CANCERS IN WHICH INACTIVATION OF ONE OR MORE TUMOR SUPPRESSOR GENES IS THOUGHT TO CONTRIBUTE TO TUMORIGENESIS. RECENT EVIDENCE SUGGESTS THAT THE GENE RESPONSIBLE FOR NEUROFIBROMATOSIS, TYPE 1 (NF-1), BELONGS TO THIS CLASS OF HERITABLE CANCER GENES. CHILDREN WITH NF-1 SHOW AN INCREASED INCIDENCE OF MYELOID LEUKEMIA, INCLUDING JUVENILE CHRONIC MYELOGENOUS LEUKEMIA (JCML) AND, PERHAPS, THE MYELOPROLIFERATIVE SYNDROME (MPS) ASSOCIATED WITH BONE MARROW MONOSOMY 7 (MO 7). WE HAVE INVESTIGATED FIVE CHILDREN WITH MO 7: THREE WITH NF-1 AND TWO OTHERS WITH SUGGESTIVE EVIDENCE OF NF-1. SOUTHERN BLOTTING EXPERIMENTS PERFORMED IN FOUR PATIENTS SHOWED NO LOSS OF HETEROZYGOSITY IN BONE MARROW SPECIMENS USING PROBES LINKED TO THE NF-1 LOCUS ON THE LONG ARM OF CHROMOSOME 17. BOTH OF OUR PATIENTS WITH FAMILIAL NF-1 INHERITED THE DISEASE FROM THEIR MOTHERS, AS DID 14 OF 19 OTHER CASES OF MYELOID LEUKEMIA IN CHILDREN WITH FAMILIAL NF-1. SEVENTEEN OF THESE 21 CHILDREN WERE BOYS. MYELOID LEUKEMIA DEVELOPED IN 12 BOYS AND FOUR GIRLS WHO INHERITED NF-1 FROM THEIR MOTHERS, AND IN FIVE BOYS WHO INHERITED THE DISEASE FROM THEIR FATHERS. FATHER-TO-DAUGHTER TRANSMISSION WAS NOT OBSERVED. TAKEN TOGETHER, THE PRESENCE OF CHROMOSOME 7 DELETIONS IN THE LEUKEMIAS OF CHILDREN WITH NF-1, A PATTERN OF INHERITANCE FAVORING MATERNAL TRANSMISSION OF NF-1, AND THE MARKED PREDILECTION FOR BOYS TO DEVELOP JCML AND MO 7 SUGGEST A MULTISTEP MECHANISM OF ONCOGENESIS IN WHICH EPIGENETIC FACTORS MIGHT PLAY A ROLE. FURTHER INVESTIGATION IS REQUIRED TO DETERMINE IF THE NF-1 GENES IN THE LEUKEMIC BONE MARROWS OF THESE PATIENTS HAVE ACQUIRED POINT MUTATIONS OR SMALL DELETIONS. 1992 17 3111 14 GENOTYPE-PHENOTYPE INTERACTIONS IN THE MYELOPROLIFERATIVE NEOPLASMS. THE CHRONIC MYELOPROLIFERATIVE NEOPLASMS (MPNS) ARE CLONAL DISORDERS CHARACTERIZED BY OVERPRODUCTION OF MATURE MYELOID CELLS. THEY SHARE ASSOCIATIONS WITH MOLECULAR ABNORMALITIES SUCH AS THE JAK2V617F MUTATION BUT ARE DISTINGUISHED BY IMPORTANT PHENOTYPIC DIFFERENCES. THIS REVIEW FIRST CONSIDERS THE FACTORS THAT MAY INFLUENCE PHENOTYPE IN JAK2-MUTATED MPNS, ESPECIALLY POLYCYTHEMIA VERA (PV) AND ESSENTIAL THROMBOCYTHEMIA (ET), AND THEN DISCUSSES THE MUTATIONS IMPLICATED IN JAK2-NEGATIVE MPNS SUCH AS IN MPL AND EPIGENETIC REGULATORS. CURRENT EVIDENCE SUPPORTS A MODEL WHERE ET AND PV ARE DISORDERS OF RELATIVELY LOW GENETIC COMPLEXITY, WHEREAS EVOLUTION TO MYELOFIBROSIS OR BLAST-PHASE DISEASE REFLECTS ACCUMULATION OF A HIGHER MUTATION BURDEN. 2012 18 2981 18 GENETIC COMPLEXITY OF CHRONIC MYELOMONOCYTIC LEUKEMIA. IN RECENT YEARS CMML HAS RECEIVED INCREASED ATTENTION AS THE MOST COMMONLY OBSERVED MDS/MPN OVERLAP SYNDROME. RENEWED INTEREST HAS OCCURRED IN PART DUE TO WIDESPREAD ADOPTION OF NEXT-GENERATION SEQUENCING PANELS THAT HELP RENDER THE DIAGNOSIS IN THE ABSENCE OF MORPHOLOGIC DYSPLASIA. ALTHOUGH MOST CMML PATIENTS EXHIBIT SOMATIC MUTATIONS IN EPIGENETIC MODIFIERS, SPLICEOSOME COMPONENTS, TRANSCRIPTION FACTORS AND SIGNAL TRANSDUCTION GENES, IT IS INCREASINGLY CLEAR THAT A SMALL SUBSET HARBORS AN INHERITED PREDISPOSITION TO CMML AND OTHER MYELOID NEOPLASMS. MORE INTRIGUING IS THE FACT THAT THE MUTATIONAL SPECTRUM OBSERVED IN CMML IS FOUND IN OTHER TYPES OF MYELOID LEUKEMIAS, BEGGING THE QUESTION OF HOW SIMILAR GENETIC BACKGROUNDS CAN LEAD TO SUCH DIVERGENT CLINICAL PHENOTYPES. IN THIS REVIEW WE PRESENT A CONTEMPORARY SNAPSHOT OF THE GENETIC COMPLEXITY INHERENT TO CMML, EXPLORE THE RELATIONSHIP BETWEEN GENOTYPE-PHENOTYPE AND PRESENT A STEPWISE MODEL OF CMML PATHOGENESIS AND PROGRESSION. 2021 19 1311 20 DEFINITIONS, BIOLOGY, AND CURRENT THERAPEUTIC LANDSCAPE OF MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS. MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASMS (MDS/MPN) ARE HEMATOLOGICAL DISORDERS CHARACTERIZED BY BOTH PROLIFERATIVE AND DYSPLASTIC FEATURES. ACCORDING TO THE 2022 INTERNATIONAL CONSENSUS CLASSIFICATION (ICC), MDS/MPN CONSISTS OF CLONAL MONOCYTOSIS OF UNDETERMINED SIGNIFICANCE (CMUS), CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), ATYPICAL CHRONIC MYELOID LEUKEMIA (ACML), MDS/MPN WITH SF3B1 MUTATION (MDS/MPN-T-SF3B1), MDS/MPN WITH RING SIDEROBLASTS AND THROMBOCYTOSIS NOT OTHERWISE SPECIFIED (MDS/MPN-RS-T-NOS), AND MDS/MPN-NOS. THESE DISORDERS EXHIBIT A DIVERSE RANGE OF GENETIC ALTERATIONS INVOLVING VARIOUS TRANSCRIPTION FACTORS (E.G., RUNX1), SIGNALING MOLECULES (E.G., NRAS, JAK2), SPLICING FACTORS (E.G., SF3B, SRSF2), AND EPIGENETIC REGULATORS (E.G., TET2, ASXL1, DNMT3A), AS WELL AS SPECIFIC CYTOGENETIC ABNORMALITIES (E.G., 8 TRISOMIES, 7 DELETIONS/MONOSOMIES). CLINICAL STUDIES EXPLORING THERAPEUTIC OPTIONS FOR HIGHER-RISK MDS/MPN OVERLAP SYNDROMES MOSTLY INVOLVE HYPOMETHYLATING AGENTS, BUT OTHER TREATMENTS SUCH AS LENALIDOMIDE AND TARGETED AGENTS SUCH AS JAK INHIBITORS AND INHIBITORS TARGETING PARP, HISTONE DEACETYLASES, AND THE RAS PATHWAY ARE UNDER INVESTIGATION. WHILE THESE TREATMENT MODALITIES CAN PROVIDE PARTIAL DISEASE CONTROL, ALLOGENEIC BONE MARROW TRANSPLANTATION (ALLO-BMT) IS THE ONLY POTENTIALLY CURATIVE OPTION FOR PATIENTS. IMPORTANT PROGNOSTIC FACTORS CORRELATING WITH OUTCOMES AFTER ALLO-BMT INCLUDE COMORBIDITIES, SPLENOMEGALY, KARYOTYPE ALTERATIONS, AND THE BONE MARROW BLASTS PERCENTAGE AT THE TIME OF TRANSPLANTATION. FUTURE RESEARCH IS IMPERATIVE TO OPTIMIZING THERAPEUTIC STRATEGIES AND ENHANCING PATIENT OUTCOMES IN MDS/MPN NEOPLASMS. IN THIS REVIEW, WE SUMMARIZE MDS/MPN DIAGNOSTIC CRITERIA, BIOLOGY, AND CURRENT AND FUTURE TREATMENT OPTIONS, INCLUDING BONE MARROW TRANSPLANTATION. 2023 20 6442 21 THERAPEUTIC APPROACHES IN MYELOFIBROSIS AND MYELODYSPLASTIC/MYELOPROLIFERATIVE OVERLAP SYNDROMES. THE DISCOVERY OF JAK2 (V617F) A DECADE AGO LED TO OPTIMISM FOR A RAPIDLY DEVELOPING TREATMENT REVOLUTION IN PH(-) MYELOPROLIFERATIVE NEOPLASMS. UNLIKE BCR-ABL, HOWEVER, JAK2 WAS FOUND TO HAVE A MORE HETEROGENEOUS ROLE IN CARCINOGENESIS. THEREFORE, FOR YEARS, DEVELOPMENT OF NEW THERAPIES WAS SLOW, DESPITE STANDARD TREATMENT OPTIONS THAT DID NOT ADDRESS THE OVERWHELMING SYMPTOM BURDEN IN PATIENTS WITH PRIMARY MYELOFIBROSIS (MF), POST-ESSENTIAL THROMBOCYTHEMIA MF, POST-POLYCYTHEMIA VERA MF, AND MYELODYSPLASTIC SYNDROME (MDS)/MYELOPROLIFERATIVE NEOPLASM (MPN) SYNDROMES. JAK-STAT INHIBITORS HAVE CHANGED THIS, DRASTICALLY AMELIORATING SYMPTOMS AND ULTIMATELY BEGINNING TO SHOW EVIDENCE OF IMPACT ON SURVIVAL. NOW, THE GENETIC FOUNDATIONS OF MYELOFIBROSIS AND MDS/MPN ARE RAPIDLY BEING ELUCIDATED AND CONTRIBUTING TO TARGETED THERAPY DEVELOPMENT. THIS HAS BEEN EMPOWERED THROUGH UPDATED RESPONSE CRITERIA FOR MDS/MPN AND REFINED PROGNOSTIC SCORING SYSTEMS IN THESE DISEASES. THE AIM OF THIS ARTICLE IS TO SUMMARIZE CONCISELY THE CURRENT AND RATIONALLY DESIGNED INVESTIGATIONAL THERAPEUTICS DIRECTED AT JAK-STAT, HEDGEHOG, PI3K-AKT, BONE MARROW FIBROSIS, TELOMERASE, AND ROGUE EPIGENETIC SIGNALING. THE REVOLUTION IN IMMUNOTHERAPY AND NOVEL TREATMENTS AIMED AT PREVIOUSLY UNTARGETED SIGNALING PATHWAYS PROVIDES HOPE FOR CONSIDERABLE ADVANCEMENT IN THERAPY OPTIONS FOR THOSE WITH CHRONIC MYELOID DISEASE. 2016