MPL W515 and JAK2 V617 mutation analysis in patients with refractory anemia with ringed sideroblasts and an elevated platelet count

Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Haematologica (Impact Factor: 5.81). 01/2007; 91(12 Suppl):ECR57.
Source: PubMed


Discovery of a constitutively activating point mutation of the Janus kinase 2 (JAK2) receptor-associated tyrosine kinase in patients with polycythemia vera (PV) and other BCR/ABL-negative myeloproliferative disorders prompted many groups around the world to examine diverse subsets of patients with myeloid diseases for the prevalence of the JAK2 V617F mutation and its clinical and pathological associations.

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Available from: David Steensma, Dec 06, 2014
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    • "Refractory anaemia with ringed sideroblasts associated with chronic thrombocytosis (RARS-T) provides a provisional entity within this group that has no specific cytogenetic or molecular findings known as yet. Recently, JAK2 V617F or MPL W515L mutations have been described in RARS-T (Steensma et al, 2006; Malcovati & Cazzola, 2008). There is accumulating evidence that JAK2 V617F can combine with other stem cell defects, as could be demonstrated for JAK2 V617F -mutated CMPD with concurrent MPL W515K/L mutation (Pardanani et al, 2006; Hussein et al, 2009) or BCR-ABL1 junction (Hussein et al, 2007a). "

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    • "Detection of both ring sideroblasts and thrombocytosis is straightforward (though exclusion of non-clonal causes of thrombocytosis is not – see below), and given the apparent rarity of this proposed new diagnostic category (Bain, 2006), it was not extensively scrutinised, at least at first. However, since 2006, several investigators have reported that clonally restricted JAK2 V617F or MPL W515 mutations are detectable in a large proportion of RARS-T cases, and that these mutations are found at a similar frequency in RARS-T and ET (Table I) (Boissinot et al, 2006; Ceesay et al, 2006; Remacha et al, 2006; Renneville et al, 2006; Steensma et al, 2006; Szpurka et al, 2006; Wang et al, 2006; Gattermann et al, 2007; Schmitt-Graeff et al, 2008; Schnittger et al, 2008). JAK2 and MPL mutations are a feature of BCR-ABL1-negative MPN, and are only rarely found in MDS (<5% of cases) (Levine et al, 2005; Steensma et al, 2005; Nishii et al, 2007). "
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    ABSTRACT: Both the 2001 World Health Organisation (WHO) classification of haematopoietic neoplasms and the 2008 WHO classification revision include a distinctive diagnostic category, refractory anaemia with ring sideroblasts and thrombocytosis (RARS-T), to describe those rare patients who have both >or=15% ring sideroblasts and a sustained elevated platelet count. Recently, it has become clear that patients meeting WHO criteria for RARS-T have clonal JAK2(V617F) and MPL(W515) mutations at a similar rate to essential thrombocythaemia (ET). Given that the provisional classification of RARS-T as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndrome, rather than as a form of MPN (i.e., ET), rests principally upon the presence of ring sideroblasts, which are a non-specific morphological finding, these new molecular results prompt reconsideration of the necessity for a distinctive RARS-T category. Here we review the historical developments that led up the definition of RARS-T as a disease entity, and we discuss conceptual understanding of RARS-T and arguments against continued use of RARS-T as a separate diagnostic category.
    Full-text · Article · Dec 2008 · British Journal of Haematology
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    ABSTRACT: Refractory anemia with ringed sideroblasts and marked thrombocytosis (RARS-T) was recently shown to be a JAK2-V617F mutation-related disorder. To determine the frequency and the prognostic significance of this mutation, we retrospectively evaluated 23 patients with platelet counts more than 600 x 10(9)/L, 15% ringed sideroblasts or more, and at least erythroid marrow dysplasia. An allele-specific polymerase chain reaction for JAK2-V617F was used to determine the allelic ratio of the mutated JAK2 allele in DNA samples extracted from bone marrow biopsies. Hematologic and survival data of the JAK2-V617F positive vs. the JAK2-V617F negative patients were statistically analyzed. Allele-specific polymerase chain reaction was also used to screen for MPL-W515 mutations. The JAK2-V617F mutation was present in 11 patients (48%) and was associated with significantly higher erythrocyte and white blood cell counts (p=0.009 and 0.011, respectively). In 6/11 RARS-T patients the allelic ratio of JAK2-V617F was above 50%, indicating the presence of cells homozygous for the mutation. In two of these patients a transition from JAK2-V617F heterozygosity to homozygosity was documented and was accompanied by rising platelet counts in sequential samples. The MPL-W515L mutation was detected in one JAK2-V617F negative patient. The relative risk of death was found to be lower in the mutation-positive group than in the mutation-negative group. RARS-T patients with JAK2-V617F have a more favorable prognosis than those without the JAK2 mutation. The prevalence of homozygous JAK2-V617F mutation in RARS-T suggests that this entity is biologically distinct from essential thrombocythemia.
    Preview · Article · Feb 2008 · Haematologica
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