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: 10.45). 11/2006; 108(7):2173-81. DOI: 10.1182/blood-2006-02-005751
Source: PubMed


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.

  • Source
    • "These patients have features of both MDS and MPN. It was recently shown that 6 out of 9 (67%) patients with RARS-t have JAK2V617F mutation [54]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: JAK-STAT (Janus associated kinase-signal transducer and activator of transcription) pathway plays a critical role in transduction of extracellular signals from cytokines and growth factors involved in hematopoiesis, immune regulation, fertility, lactation, growth and embryogenesis. JAK family contains four cytoplasmic tyrosine kinases, JAK1-3 and Tyk2. Seven STAT proteins have been identified in human cells, STAT1-6, including STAT5a and STAT5b. Negative regulators of JAK-STAT pathways include tyrosine phosphatases (SHP1 and 2, CD45), protein inhibitors of activated STATs (PIAS), suppressors of cytokine signaling (SOCS) proteins, and cytokine-inducible SH2-containing protein (CIS). Dysregulation of JAK-STAT pathway have been found to be key events in a variety of hematological malignancies. JAK inhibitors are among the first successful agents reaching clinical application. Ruxolitinib (Jakafi), a non-selective inhibitor of JAK1 & 2, has been approved by FDA for patients with intermediate to high risk primary or secondary myelofibrosis. This review will also summarize early data on selective JAK inhibitors, including SAR302503 (TG101348), lestaurtinib (CEP701), CYT387, SB1518 (pacritinib), LY2784544, XL019, BMS-911543, NS-018, and AZD1480.
    Full-text · Article · Jan 2013
  • Source
    • "The JAK2 V617F mutation has been observed in up to 98% of patients with PV and 50–60% of patients with ET and PMF. With the exception of the syndrome 'refractory anaemia with ringed sideroblasts associated with marked thrombocytosis' (RARS-T) where it is observed in approximately one half of patients (Szpurka et al, 2006; Schmitt-Graeff et al, 2008), the JAK2 V617F mutation is uncommon in other myeloid disorders, such as myelodysplastic syndrome, chronic myelomonocytic "
    [Show abstract] [Hide abstract]
    ABSTRACT: Molecular genetic assays for the detection of the JAK2 V617F (c.1849G>T) and other pathogenetic mutations within JAK2 exon 12 and MPL exon 10 are part of the routine diagnostic workup for patients presenting with erythrocytosis, thrombocytosis or otherwise suspected to have a myeloproliferative neoplasm. A wide choice of techniques are available for the detection of these mutations, leading to potential difficulties for clinical laboratories in deciding upon the most appropriate assay, which can lead to problems with inter-laboratory standardization. Here, we discuss the most important issues for a clinical diagnostic laboratory in choosing a technique, particularly for detection of the JAK2 V617F mutation at diagnosis. The JAK2 V617F detection assay should be both specific and sensitive enough to detect a mutant allele burden as low as 1-3%. Indeed, the use of sensitive assays increases the detection rate of the JAK2 V617F mutation within myeloproliferative neoplasms. Given their diagnostic relevance, it is also beneficial and relatively straightforward to screen JAK2 V617F negative patients for JAK2 exon 12 mutations (in the case of erythrocytosis) or MPL exon 10 mutations (thrombocytosis or myelofibrosis) using appropriate assays. Molecular results should be considered in the context of clinical findings and other haematological or laboratory results.
    Full-text · Article · Oct 2012 · British Journal of Haematology
  • Source
    • "(Abdel-Wahab et al, 2009; Delhommeau et al, 2009; Jankowska et al, 2009; Kosmider et al 2009, Tefferi, et al 2009), RUNX1 (Ernst et al, 2010; Gelsi-Boyer et al, 2008; Kuo et al, 2009), JAK2 (Jelinek et al, 2005; Renneville et al, 2006; Steensma et al, 2005; Szpurka et al, 2006; Tyner et al, 2009), ASXL1 (Boultwood et al, 2010a; Gelsi-Boyer et al, 2009) and/or CBL (Dunbar et al, 2008; Grand et al, 2009; Loh et al, 2009; Makishima et al, 2009; Sanada et al, 2009). Only studies reporting data for 5 CMML or more were taken into account. "
    [Show abstract] [Hide abstract]
    ABSTRACT: JMML and CMML are rare myelodysplastic/myeloproliferative neoplasms occurring at both ends of life. To investigate relationships between JMML and CMML, genes recently involved in CMML were studied in 68 JMML patients. Mutations in TET2, RUNX1 and JAK2(V617F) are involved in myelodysplastic and/or myeloproliferative syndromes, and more specifically in CMML but were not found in JMML. Pangenomic analysis by SNP-array showed no abnormality at these loci. Three frameshift mutations of ASXL1 leading to a truncated protein were found in three patients (4%) with late onset JMML displaying also RAS activating mutations. Homozygous mutations of CBL with 11q loss of heterozygosity were found in five (7%) JMML. CBL substitutions were different from those reported in CMML, exclusive from other RAS activating mutations, and were germline in all patients. Overall, the pattern of genetic lesions observed in JMML differed from that of CMML. Although signalling deregulation is involved in CMML, transcriptional deregulation seems to play a pivotal role, with mutation of RUNX1, ASXL1 or TET2. Conversely, none of these genes involved in transcription or chromatin remodelling was found to be significantly altered in JMML, while CBL mutations confirm the central role of RAS and growth factor signalling deregulation in JMML.
    Full-text · Article · Oct 2010 · British Journal of Haematology
Show more