Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation

Experimental Hematology and Hematopoiesis Section, R40, Taussig Cancer Center R-40, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA.
Blood (Impact Factor: 9.78). 11/2006; 108(7):2173-81. DOI: 10.1182/blood-2006-02-005751
Source: PubMed

ABSTRACT JAK2 V617F mutation recently was identified as a pathogenic factor in typical chronic myeloproliferative diseases (CMPD). Some forms of myelodysplastic syndromes (MDS) show a significant overlap with CMPD (classified as MDS/MPD), but the diagnostic assignment may be challenging. We studied blood or bone marrow from 270 patients with MDS, MDS/MPD, and CMPD for the presence of JAK2 V617F mutation using polymerase chain reaction, sequencing, and melting curve analysis. The detection rate of JAK2 V617F mutants for polycythemia vera, chronic idiopathic myelofibrosis, and essential thrombocythemia (n = 103) was similar to the previously reported results. In typical forms of MDS (n = 89) JAK2 V617F mutation was very rare (n = 2). However, a higher prevalence of this mutation was found in patients with MDS/MPD-U (9 of 35). Within this group, most of the patients harboring JAK2 V617F mutation showed features consistent with the provisional MDS/MPD-U entity refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T). Among 9 RARS-T patients, 6 showed the presence of JAK2 V617F mutation, and in 1 patient without mutation, aberrant, positive phospho-STAT5 staining was seen that is typically present in association with JAK2 V617F mutation. In summary, we found that RARS-T reveals a high frequency of JAK2 V617F mutation and likely constitutes another JAK2 mutation-associated form of CMPD.

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    ABSTRACT: Background The presence of somatic mutations in splicing factor 3b subunit 1 (SF3B1) in patients with Myelodysplastic syndromes with ring sideroblasts (MDS-RS) highlights the importance of the RNA-splicing machinery in MDS. We previously reported the presence of bone marrow (BM) RS in Sf3b1 heterozygous (Sf3b1 +/¿) mice which are rarely found in mouse models of MDS. Sf3b1 +/¿ mice were originally engineered to study the interaction between polycomb genes and other proteins.Methods We used routine blood tests and histopathologic analysis of BM, spleen, and liver to evaluate the hematologic and morphologic characteristics of Sf3b1 +/¿ mice in the context of MDS by comparing the long term follow-up (15 months) of Sf3b1 +/¿ and Sf3b1 +/+ mice. We then performed a comprehensive RNA-sequencing analysis to evaluate the transcriptome of BM cells from Sf3b1 +/¿ and Sf3b1 +/+ mice.Results Sf3b1 +/¿ exhibited macrocytic anemia (MCV: 49.5¿±¿1.6 vs 47.2¿±¿1.4; Hgb: 5.5¿±¿1.7 vs 7.2¿±¿1.0) and thrombocytosis (PLTs: 911.4¿±¿212.1 vs 878.4¿±¿240.9) compared to Sf3b1 +/+ mice. BM analysis showed dyserythropoiesis and occasional RS in Sf3b1 +/¿ mice. The splenic architecture showed increased megakaryocytes with hyperchromatic nuclei, and evidence of extramedullary hematopoiesis. RNA-sequencing showed higher expression of a gene set containing Jak2 in Sf3b1 +/¿ compared to Sf3b1 +/+.Conclusions Our study indicates that Sf3b1 +/¿ mice manifest features of low risk MDS-RS and may be relevant for preclinical therapeutic studies.
    Journal of Hematology & Oncology 12/2014; 7(1):89. DOI:10.1186/s13045-014-0089-x · 4.93 Impact Factor
  • Haematologica 11/2014; 99(11):1650-2. DOI:10.3324/haematol.2014.113944 · 5.87 Impact Factor
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    ABSTRACT: Myelodysplastic syndromes (MDS) are a group of clonal disorders arising from hematopoietic stem cells generally characterized by inefficient hematopoiesis, dysplasia in one or more myeloid cell lineages, and variable degrees of cytopenias. Most MDS patients are diagnosed in their late 60s to early 70s. The estimated incidence of MDS in the United States and in Europe are 4.3 and 1.8 per 100,000 individuals per year, respectively with lower rates reported in some Asian countries and less well estimated in other parts of the world. Evolution to acute myeloid leukemia can occur in 10-15% of MDS patients. Three drugs are currently approved for the treatment of patients with MDS: immunomodulatory agents (lenalidomide), and hypomethylating therapy [HMT (decitabine and 5-azacytidine)]. All patients will eventually lose their response to therapy, and the survival outcome of MDS patients is poor (median survival of 4.5 months) especially for patients who fail (refractory/relapsed) HMT. The only potential curative treatment for MDS is hematopoietic cell transplantation. Genomic/chromosomal instability and various mechanisms contribute to the pathogenesis and prognosis of the disease. High throughput genetic technologies like single nucleotide polymorphism array analysis and next generation sequencing technologies have uncovered novel genetic alterations and increased our knowledge of MDS pathogenesis. We will review various genetic and non-genetic causes that are involved in the pathogenesis of MDS.
    12/2014; 49(4):216-27. DOI:10.5045/br.2014.49.4.216