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. 2006 Oct 1;108(7):2173-81.
doi: 10.1182/blood-2006-02-005751. Epub 2006 Jun 1.

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

Hadrian Szpurka  1 , Ramon Tiu, Gurunathan Murugesan, Samer Aboudola, Eric D Hsi, Karl S Theil, Mikkael A Sekeres, Jaroslaw P Maciejewski
Affiliations

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

Hadrian Szpurka et al. Blood. .

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) VSports手机版. 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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Figures

Figure 1.
Figure 1.
Molecular assay for rapid identification and characterization of JAK2 V617F mutation. (A) Electrophoretogram of AS-PCR for JAK2 V617F mutation in MDS/MPD-Unclassifiable disease. In a healthy patient with the wild-type G/G genotype, only a single 364-bp band is visible (lane 9). A point mutation V617F G→T (either G/T or T/T) is indicated by the presence of a second 203-bp band. Lanes 1-2, MDS/MPD-U; lanes 3-6, RARS-T; lane 7, AML; lane 8, CMML-1; lane 9, normal negative control; lane 10, CIMF (T/T genotype) positive control. (B) Partial sequence of JAK2 exon 14 showing wild-type (G/G) sequence in a healthy patient (middle) and mutated (G/T or T/T) sequences in patient with MDS/MPD-U (right) and CIMF (left). (C) LightTyper DNA melting curves: wild type (middle) is characterized by a single peak (higher melting temperature), G/T genotype (left) by 2 peaks, and T/T genotype (right) by one peak (lower melting temperature).
Figure 2.
Figure 2.
Sensitivity of molecular assay. Sensitivity of (A) AS-PCR, (B) sequencing, and (C) LightTyper melting curves. Genomic DNA isolated from granulocytes of both healthy (G/G) and JAK2 V617F mutated (T/T) patients were mixed at varying ratios respectively: lane 1, 1:1; lane 2, 1:2; lane 3, 1:5; lane 4, 1:10; lane 5, 1:100; and lane 6, 1:500. Lane 7, healthy patient with G/G genotype; and lane 8, CIMF patient with mutated T/T genotype. The 3 methods showed similar sensitivities in detecting a mutated population at a level of 10%.
Figure 3.
Figure 3.
Frequency and type of JAK2 V617F mutation within diagnostic categories. (G/G: wild type; G/T or T/T: heterozygous or homozygous for mutation) (left panel). Within WHO MDS/MPD-U, 6 of 9 cases that were positive for JAK2 V617F mutation occurred in RARS-T. When separated from MDS/MPD-U, 67% of RARS-T cases showed a JAK2 V617F mutation, but only 12% of the remaining MDS-MPD-U were positive (right panel).
Figure 4.
Figure 4.
Immunohistochemical detection of p-STAT. Positive staining is present in nuclei of megakaryocytes and erythroid precursors (A) in a patient (Table 3, Patient no. 7) with RARS-T heterozygous for JAK2 V617F mutation (G/T). Negative antibody control (B). Positive staining is present in nuclei of erythroid precursors but absent in megakaryocytes (C) in a patient (Table 3, Patient no. 1) with RARS-T who lacks JAK2 V617F mutation. Negative antibody control (D). Original magnification, 100×.
Figure 5.
Figure 5.
Pathologic features of RARS-T heterozygous for JAK2 V617F G/T mutation. (A) Bone marrow aspirate shows frequent ringed sideroblasts (Prussian blue stain, original magnification, × 100). (B, C) Bone marrow biopsies from different patients show hypercellularity with clustered megakaryocytes (H&E stain, original magnification × 40). (D) Bone marrow biopsy with increased stromal reticulin (2+/4+) (Gomori reticulum stain, original magnification, × 40). (Panels A, B, D: Table 3, Patient no. 5; Panel C: Table 3, Patient no. 3.)
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