title: Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis.
abstract: We studied patients with myeloid neoplasm associated with ringed sideroblasts and/or thrombocytosis. The combination of ringed sideroblasts 15% or greater and platelet count of 450 x 10(9)/L or greater was found in 19 subjects fulfilling the diagnostic criteria for refractory anemia with ringed sideroblasts (RARS) associated with marked thrombocytosis (RARS-T), and in 3 patients with primary myelofibrosis. JAK2 and MPL mutations were detected in circulating granulocytes and bone marrow CD34+ cells, but not in T lymphocytes, from 11 of 19 patients with RARS-T. Three patients with RARS, who initially had low to normal platelet counts, progressed to RARS-T, and 2 of them acquired JAK2 (V617F) at this time. In female patients with RARS-T, granulocytes carrying JAK2 (V617F) represented only a fraction of clonal granulocytes as determined by X-chromosome inactivation patterns. RARS and RARS-T patient groups both consistently showed up-regulation of ALAS2 and down-regulation of ABCB7 in CD34+ cells, but several other genes were differentially expressed, including PSIP1 (LEDGF), CXCR4, and CDC2L5. These observations suggest that RARS-T is indeed a myeloid neoplasm with both myelodysplastic and myeloproliferative features at the molecular and clinical levels and that it may develop from RARS through the acquisition of somatic mutations of JAK2, MPL, or other as-yet-unknown genes.
authors.affiliation: Department of Hematology Oncology, University of Pavia & Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS), Policlinico San Matteo, Pavia, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Malcovati
authors.forename: Matteo G
authors.initials: MG
authors.lastname: Della Porta
authors.forename: Daniela
authors.initials: D
authors.lastname: Pietra
authors.forename: Emanuela
authors.initials: E
authors.lastname: Boveri
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.forename: Anna
authors.initials: A
authors.lastname: Gallì
authors.forename: Erica
authors.initials: E
authors.lastname: Travaglino
authors.forename: Angela
authors.initials: A
authors.lastname: Brisci
authors.forename: Elisa
authors.initials: E
authors.lastname: Rumi
authors.forename: Francesco
authors.initials: F
authors.lastname: Passamonti
authors.forename: Rosangela
authors.initials: R
authors.lastname: Invernizzi
authors.forename: Laura
authors.initials: L
authors.lastname: Cremonesi
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.forename: James S
authors.initials: JS
authors.lastname: Wainscoat
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000754:Anemia, Refractory, with Excess of Blasts / Q000235:genetics* / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000235:genetics; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010976:Platelet Count; D053628:Receptors, Thrombopoietin / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D013922:Thrombocytosis / Q000235:genetics* / Q000473:pathology*; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2