Refractory anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in SF3B1 or other spliceosome genes accompanied by JAK2V617F and ASXL1 mutations

Jeromin, Sabine; Haferlach, Torsten; Weissmann, Sandra; Meggendorfer, Manja; Eder, Christiane; Nadarajah, Nirsoshan; Alpermann, Tamara; Kohlmann, Alexander; Kern, Wolfgang; Haferlach, Claudia; Schnittger, Susanne

doi:10.3324/haematol.2014.119032

Cited by 69 publications

(92 citation statements)

References 14 publications

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“…While it is important to distinguish RARS-T from ET with BM RS and RARS with reactive thrombocytosis, this distinction is often difficult based on morphology alone. Molecular testing has defined a unique mutational landscape in patients with RARS-T. Common mutations include; SF3B1 ( 90%), JAK2V617F ( 50%), TET2 ( 25%), DNMT3A ( 15%) and ASXL1 ( 15%) [3]. In the current study, the mutational frequencies were SF3B1285%, JAK2V617F-33%, ASXL1-29%, DNMT3A-13%, SETBP1-13%, and TET2-10%.…”

Section: Discussionsupporting

confidence: 46%

“…Common cytogenetic abnormalities included; trisomy 8 (n 5 3) (4%), complex/monosomal karyotype (n 5 3) (4%), and one case each ofdel(5q31), del(7q), del(20q), and inv(3)(q21q26.2). There were two non-recurrent balanced chromosomal translocations seen; 46, XY, t(13;14) (q10;q10) [20] and 46, XX, t(7;8) (q21;q23) [3]. There was no significant correlation between the occurrence of cytogenetic abnormalities and the ASXL1 mutational status (P 5 0.13) ( Table I).…”

Section: Resultsmentioning

confidence: 94%

“…In 2008, the minimum platelet count required for inclusion was lowered from 600 to 450 3 10(9)/L for consistency with the diagnostic criteria for essential thrombocythemia (ET) [1]. The median age at diagnosis ranges from 71 to 75 years and approximately 80% of patients do not have detectable clonal cytogenetic abnormalities [3,4]. The advent of next-generation sequencing (NGS) has helped define the molecular landscape of patients with RARS-T. Common abnormalities include: spliceosome component mutations-SF3B1 90%, SRSF2 7%, U2AF1 5%, ZRSR2 3%; signal pathway mutations-JAK2V617F 57%, MPL 3%, CBL 4%; mutations in epigenetic regulator genes-ASXL1 15%, TET2 25%, EZH2 7%, DNMT3A 15%, IDH2 4%, and mutations involving transcription factors-ETV6 3%, RUNX1 1% [3,4].…”

Section: Introductionmentioning

confidence: 99%

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Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

et al. 2016

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Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had 1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n 5 82), anemia (P 5 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P 5.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n 5 48), univariate analysis showed association between poor survival and presence of SETBP1 (P 5 0.04) or ASXL1 (P 5 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P 5 0.04); the number of concurrent mutations did not provide additional prognostication (P 5 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high ( 2 points), with median survivals of 80, 42 and 11 months respectively (P 5 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutationenhanced prognostic model.

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Section: Discussionsupporting

confidence: 46%

Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

et al. 2016

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“…Chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical BCR-ABL1-negative chronic myeloid leukemia, MDS/MPN unclassifiable, refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) are included (19). The patient in the present case was carrier of a JAK2 (V617F) mutation, which is more common in ET compared with MDS patients (3,16,(19)(20)(21)(22). The JAK2 (V617F) mutation is described in >95% of polycythemia vera and 50-60% of ET and myelofibrosis patients.…”

Section: Discussionmentioning

confidence: 94%

“…However, in cases with the absence of ring sideroblasts, the MDS diagnosis is challenging and it may confound with myeloproliferative disorders (MPD), mainly if there is a Janus kinase 2 gene (JAK2) V617F mutation (16). This abnormality is much more common in this group of disorders compared to MDS.…”

Section: Introductionmentioning

confidence: 99%

Myelodysplastic syndrome without ring sideroblasts and with Janus kinase 2 gene mutation: An unusual case report

Ornellas¹,

Silva²,

Solza

et al. 2016

Molecular and Clinical Oncology

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Abstract. Myelodysplastic syndrome (MDS) cases comprise a heterogeneous group of hematological disorders that are characterized by impaired hematopoiesis, with cytopenias of different grades and risk of developing acute myeloid leukemia. MDS may rarely be associated with thrombocytosis. In such cases, myelodysplasia and myeloproliferative disorders may overlap, making correct diagnosis difficult. We herein describe a case of MDS with thrombocytosis, Janus kinase 2 gene mutation-positive and Perls' staining-negative, which was initially classified as essential thrombocythemia (ET). This case highlights that MDS may be misdiagnosed as ET and inappropriate treatment may be initiated. Therefore, it is crucial to carefully combine all available data on morphology and immunophenotyping, and to perform the necessary molecular, cytogenetic and molecular cytogenetic analyses, in order to correctly diagnose this disease.

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Refractory anemia with ring sideroblasts and RARS with thrombocytosis

Patnaik

Tefferi

2015

American J Hematol

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Disease Overview: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS‐T). Diagnosis: RARS is a lower risk myelodysplastic syndrome (MDS) with dysplasia limited to the erythroid lineage, <5% bone marrow (BM) blasts and ≥15% BM RS. RARS‐T is a provisional entity in the MDS/MPN (myeloproliferative neoplasm) overlap syndromes, with diagnostic features of RARS, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes similar to those observed in BCR‐ABL1 negative MPN. Mutations and Karyotype: Mutations in the SF3B1 gene are seen in ≥80% of patients with RARS and RARS‐T, and strongly correlate with the presence of BM RS; RARS‐T patients have additional mutations such as, JAK2V617F (∼60%), MPL (<5%), and CALR (<5%). Cytogenetic abnormalities are uncommon in both RARS and RARS‐T. Risk stratification: Most patients with RARS are stratified into lower risk groups by the International Prognostic Scoring System (IPSS) for MDS and the revised IPSS. Disease outcome in RARS‐T is better than that of RARS, but worse than that of essential thrombocytosis. Both RARS and RARS‐T have a low risk of leukemic transformation. Treatment: Anemia and iron overload are complications in both diseases and are managed similar to lower risk MDS. Aspirin therapy is reasonable in RARS‐T, especially in the presence of JAK2V617F, but the value of platelet‐lowering drugs is uncertain. Case reports of RARS‐T therapy with lenalidomide warrant additional studies. Am. J. Hematol. 90:550–559, 2015. © 2015 Wiley Periodicals, Inc.

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Refractory anemia with ring sideroblasts and marked thrombocytosis cases harbor mutations in SF3B1 or other spliceosome genes accompanied by JAK2V617F and ASXL1 mutations

Cited by 69 publications

References 14 publications

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

Myelodysplastic syndrome without ring sideroblasts and with Janus kinase 2 gene mutation: An unusual case report

Refractory anemia with ring sideroblasts and RARS with thrombocytosis

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