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Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis with Cooccurrent SF3B1 and MPL Ge

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Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis with Cooccurrent SF3B1 and MPL Ge Myelodysplastic Syndrome/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis with Cooccurrent SF3B1 and MPL Gene Mutations: A Case Report and Brief Review Downloaded from https://academic.oup.com/labmed/article/51/3/315/5681672 by guest on 01 October 2021 of the Literature Chang-Hun Park, MD,1 Jae Won Yun, MD, PhD2 Hyun-Young Kim, MD,2,3 Ki-O Lee, AS,4 Sun-Hee Kim, MD, PhD2 Hee-Jin Kim, MD, PhD 2* Laboratory Medicine 2020;51:315-319 DOI: 10.1093/labmed/lmz076 ABSTRACT Background: Myelodysplastic syndrome/myeloproliferative neoplasm mutations in MPN disease (JAK2 V617F/exon 12, CALR gene exon 9, with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a new and MPL gene exon 10 mutations). disease entity in the current WHO classification. Genetically, 60%–90% of cases have mutations in SF3B1, strongly associated with RS, and more Results: The molecular study revealed SF3B1 K666T and MPL W515R than half of them cooccur with JAK2 V617F. This report describes the mutations, while BCR-ABL1 or JAK2 V617F/exon 12 and CALR rare case of MDS/MPN-RS-T with SF3B1 mutation cooccurring with an mutations were all negative. MPL mutation. Methods: We report a 79-year-old man who was referred because Conclusion: This is a rare case of concomitant SF3B1 and MPL of generalized edema. Peripheral blood testing showed macrocytic mutations in MDS/MPN-RS-T. anemia and thrombocytosis, and bone marrow analysis demonstrated dyserythropoiesis with RS and increased megakaryocytes. A molecular Keywords: myelodysplastic syndrome, myeloproliferative neoplasm, ring study was performed to detect SF3B1 mutations and recurrent sideroblasts, thrombocytosis, SF3B1, MPL Myelodysplastic syndrome/myeloproliferative neoplasm and thrombocytosis (RARS-T), is a new disease entity in the with ring sideroblasts and thrombocytosis (MDS/MPN- current WHO classification of hematologic malignancies.1,2 RS-T), formerly referred to as refractory anemia with RS Hematologically, MDS/MPN-RS-T has features of both MDS and MPN, having dysplasia with increased ring sideroblasts Abbreviations: (≥15%) and thrombocytosis (platelet count, ≥450 × 109/L).1 MDS/MPN-RS-T, myelodysplastic syndrome/myeloproliferative neoplasm It is a rare disease and has a relatively indolent course with ring sideroblasts and thrombocytosis; RARS-T, refractory anemia with RS and thrombocytosis; CBCs, complete blood counts; Hb, hemoglobin; MCV, compared to other MDS/MPN diseases, such as chronic mean corpuscular volume; WBC, white blood cell; FISH, fluorescence in situ myelomonocytic leuekemia and atypical chronic myeloid hybridization; ET, essential thrombasthenia; PMF, primary myelofibrosis; leukemia.3 W515, tryptophan 515; AML, acute myeloid leukemia; BM, bone marrow. 1Department of Laboratory Medicine & Genetics, Samsung Changwon Genetically, mutations in the SF3B1 gene are the most fre- Hospital, Sungkyunkwan University School of Medicine, Changwon, quent molecular defect in MDS/MPN-RS-T (60%~90%).1,4,5 2 Korea, Department of Laboratory Medicine & Genetics, Samsung Medical The SF3B1 gene encodes subunit 1 of the splicing factor Center, Sungkyunkwan University School of Medicine, Seoul, Korea, 3 3b protein, and the SF3B1 mutant has a strong genotype– Department of Laboratory Medicine, Gyeongsang National University Hospital, Jinju, Korea, 4Samsung Biomedical Research Institute, Samsung phenotype correlation with the presence of RS. On the other Medical Center, Seoul, Korea. hand, genes mutated in MPN diseases are also commonly affected, with the JAK2 V617F mutation detected in ~60% of *To whom correspondence should be addressed. [email protected] cases. Approximately half of patients with MDS/MPN-RS-T © American Society for Clinical Pathology 2019. All rights reserved. For permissions, please e-mail: [email protected] 315 Case Study have concomitant SF3B1 and JAK2 V617F mutations.4 Unlike JAK2 V617F, other MPN mutations, such as MPL and CALR mutations, are infrequent in MDS/MPN-RS-T.6,7 In this article, we report the rare case of concomitant SF3B1 and MPL mutations in a patient with MDS/MPN-RS-T; also, clinical and molecular findings are discussed. Downloaded from https://academic.oup.com/labmed/article/51/3/315/5681672 by guest on 01 October 2021 Clinical History A 79-year-old man was referred to our hospital because of generalized edema. He had a past medical history of benign prostatic hyperplasia. Mild splenomegaly was detected on abdominal computed tomography. Laboratory Information The peripheral blood smear showed macrocytic anemia with anisopoikilocytosis (teardrop cells, elliptocytes, and acanthocytes), left-shifted neutrophils with eosinophilia, and thrombocytosis. Complete blood counts (CBCs) were hemoglobin (Hb) of 116 g/L, with an increased mean cor- puscular volume (MCV) 101.8 fL, white blood cell (WBC) count of 7.74 × 109/L (myelocytes, 2%; band, 5%; neu- trophils, 44%; monocytes, 10%; lymphocytes, 11%; and eosinophils, 29%), and platelets of 795 × 109/L. The bone marrow study demonstrated dyserythropoiesis, increased eosinophil precursors, and increased megakaryocytes (Images 1A and 1B). Blasts were less than 5%. Iron stain revealed ring sideroblasts up to 24% (Image 1C). The cellularity was normal for age (~20%), and there was no evidence of fibrosis. A chromosome study revealed 46,XY,i(14)(q10)[10]/46,XY[10]. Fluorescence in situ hybrid- ization (FISH) analyses for FGFR1 (dual-color break-apart probe; MetaSystems, Altlussheim, Germany), PDGFRB (dual-color break-apart probe; Kreatech Diagnostics, Leica Biosystems, IL, USA), FIP1L1-PDGFRA (LSI tricolor prob; Vysis, Abbott Laboratories, Abbott Park, IL, USA), Image 1 and BCR/ABL1 (LSI dual-color translocation probe; Vysis) Bone marrow cytomorphology in the patient with myelodysplasic were performed for eosinophilia and increased eosino- syndrome/myeloproliferative neoplasm with ring sideroblasts philic precursors in bone marrow, which showed normal and thrombocytosis. Bone marrow aspirate smear showed (A) signals. megakaryocytic hyperplasia (Wright Giemsa, ×400) and (B) dyserythropoiesis with multinuclearity and increased eosinophil A molecular genetic study was performed on DNA extracted precursor (Wright Giemsa, ×1000). (C) Iron stain revealed frequent from bone marrow aspirate specimens to detect SF3B1 ring sideroblasts (Prussian blue, ×1000). 316 Lab Medicine 2020;51;315–319 www.labmedicine.com DOI: 10.1093/labmed/lmz076 Case Study gene mutations and recurrent gene mutations in MPN dis- eases (JAK2 V617F/exon 12 mutations, CALR gene exon 9 mutations, and MPL gene exon 10 mutations). PCR was performed on a thermal cycler (Applied Biosystems, Foster City, CA, USA), and direct sequencing analyses were per- formed by using the BigDye Terminator cycle sequencing ready reaction kit (Applied Biosystems) on the ABI 3100 genetic analyzer (Applied Biosystems). The primers for the experiments were designed by the authors (available upon Downloaded from https://academic.oup.com/labmed/article/51/3/315/5681672 by guest on 01 October 2021 request). In addition, reverse transcription-PCR was per- formed to detect BCR-ABL rearrangement. As a result, we detected a c.1997A>C (p.K666T) mutation in the SF3B1 gene and a c.1543T>A (p.W515R) mutation in the MPL gene. Both mutations are previously reported, rare mutations. BCR-ABL rearrangement was negative, and JAK2 V617F/exon 12 mutations and CALR gene exon 9 mu- tations were also all negative. In order to confirm the somatic nature of the SF3B1 K666T and MPL W515R mutations, we Figure 1 additionally performed targeted sequencing analyses using Detection of SF3B1 c.1997A>C (p.K666T) mutation and MPL the DNA extracted from the patient’s buccal swab speci- c.1544G>T (p.W515R) mutation in the bone marrow specimen from mens and found negative results (Figure 1). Collectively, the the patient. The mutations were negative in the DNA extracted patient was diagnosed as having MDS/MPN-RS-T. from buccal swab specimen of the patient, confirming the somatic nature. Patient Follow-Up that the patient’s bone marrow cells had a somatic SF3B1 K666T mutation and an MPL W515R mutation, and chromo- The patient received treatment with anagrelide and some analyses showed isochromosome 14q. The workup hydroxyurea. The patient is currently on follow-up for for the possibility of a concomitant clonal hematologic dis- 5 months from the diagnosis. During the 1 week of the initial order associated with eosinophilia in the patient, including anagrelide treatment, the hemoglobin level decreased from FISH for FGFR1, PDGFRA, PDGFRB, and BCR/ABL1 106 g/L to 87 g/L but shortly recovered to 103 g/L without rearrangement, were all negative. According to a study transfusion (Figure 2A). The platelet count decreased from involving 92 patients with MDS/MPN-RS-T, mutations in 828 × 109/L to 578 × 109/L after the initial week of anagrelide the spliceosome components were the most frequent, with treatment and then increased to 720 × 109/L; it then fell to the SF3B1 mutations in 90%, followed by SRSF2 mutations in reference range after combination therapy with hydroxyurea 6.7%, U2AF1 mutations in 5.3%, and ZRSR2 mutations in (Figure 2B). After 142 days from the start of anagrelide 2.7%.4 The second common group of gene mutations was treatment, the patient had to stop anagrelide therapy due to those in the signaling pathway genes, JAK2 V617F (57%), non-ST segment elevation myocardial infarction. MPL (2.7%), and CBL (4%).4 Common mutations in SF3B1 are K700E (49%), H662Q (17%), R625L (7%), K666N (5%), K666R (5%), G742D
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