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NUP98-NSD1 Driven MDS/MPN in Childhood Masquerading As JMML

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NUP98-NSD1 Driven MDS/MPN in Childhood Masquerading As JMML CLINICAL AND LABORATORY OBSERVATIONS NUP98-NSD1 Driven MDS/MPN in Childhood Masquerading as JMML Astrid Behnert, MD,*† Alex G. Lee, PhD,*† Elizabeth P. Young, MD,* 09/01/2020 on BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3yRlXg5VZA8uSeVZO4Jyms7nBsZRWzUYTPpeZo3zORAmRpmoMPh4w5Q== by https://journals.lww.com/jpho-online from Downloaded Marcus R. Breese, PhD,*† Stanley G. Leung, BA,*† Inge Behroozfard, BS,* Maria Maruffi,MD,‡ E. Alejandro Sweet-Cordero, MD,*† Downloaded Christopher C. Dvorak, MD,*† Julia Chu, MD,* and Elliot Stieglitz, MD*† from https://journals.lww.com/jpho-online blasts to rule out AML. Translocations have been reported in Summary: Overlapping myelodysplastic/myeloproliferative neoplasms JMML4,5 but the majority of patients with JMML ( > 95%) (MDS/MPN) are clonal hematopoietic disorders with features of have somatic or germline mutations detected in genes encoding myelodysplasia and myeloproliferation. The only well-characterized proteins signaling in the RAS/MAPK pathway.6 Most patients MDS/MPN in children is juvenile myelomonocytic leukemia, an with JMML receive allogeneic hematopoietic cell trans- aggressive disorder of infants and toddlers. The biochemical hallmark by plantation (HCT), which currently remains the only curative BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3yRlXg5VZA8uSeVZO4Jyms7nBsZRWzUYTPpeZo3zORAmRpmoMPh4w5Q== of this disease is hyperactivation of the Ras/MAPK signaling pathway 2 caused by mutations in Ras pathway genes in more than 90% of treatment option. Here, we report a patient who was suspected patients. Translocations involving receptor tyrosine kinases have been of having JMML but was found to have a cryptic identified in rare cases. Here, we report a 2-year-old patient who NUP98-NSD1 fusion detected on RNA sequencing (RNASeq) presented with MDS/MPN driven by a cytogenetically cryptic that has not been previously reported in MDS/MPN. NUP98-NSD1 fusion, a translocation thought to exclusively occur in patients with acute myeloid leukemia. CASE REPORT Key Words: MDS/MPN, JMML, NUP98-NSD1 A 2-year-old girl presented after 6 months of progressive – symptoms including fatigue, pallor, and gingival hyperplasia, and was (J Pediatr Hematol Oncol 2020;00:000 000) found to have severe anemia, thrombocytopenia, leukocytosis (85.2 K/µL with 20% monocytes) and elevated age-adjusted hemo- globin F (37.1%). Bone marrow aspirate revealed 5% myeloid blasts, yelodysplastic/myeloproliferative neoplasms (MDS/ increased promonocytes, dysplastic features, and absence of BCR/ ABL. Biopsy of a scalp lesion revealed a myelomonocytic infiltrate, M MPN) are clonal hematopoietic disorders characterized consistent with leukemia cutis. Abdominal ultrasound was negative by aberrant proliferation with increased immature cells in the for hepatosplenomegaly. Cytogenetic analysis showed a single peripheral blood as well as varying degrees of dysplasia and abnormal cell with a 44,X,-X,del(9)(q13q22),-16[1],46,XX[20] kar- cytopenias. These disorders have an increased risk of pro- yotype. FLT3-ITD, CEBPA,andNPM1 were tested using next gression to acute myeloid leukemia (AML) and are further generation sequencing and were all normal. An institutional DNA divided into atypical chronic myeloid leukemia, chronic mye- sequencing panel detected a mutation in NRAS p.Gly12Val at an lomonocytic leukemia, juvenile myelomonocytic leukemia allele frequency of 8%, a buccal germline sample was negative. (JMML), and a fourth category, MDS/MPN-unclassifiable, Diagnosis of JMML was suspected although the patient did not have splenomegaly at time of diagnosis and only a subclonal RAS mutation which is reserved for myeloid neoplasms not meeting diagnostic fi 1 was detected. A presumptive diagnosis of MDS/MPN-unclassi able criteria for any of the other 3. MDS/MPN is a rare diagnosis – ∼ requiring HCT was made. Granulocyte-macrophage colony- in children, occurring in 1 to 4 cases per million, best exem- stimulating factor hypersensitivity testing was not performed. plified by JMML, a frequently fatal disease in early childhood.2 Children with JMML typically present with fever, anemia, METHODS thrombocytopenia, and leukocytosis with peripheral ’ monocytosis.2 Most children also present with splenomegaly, The patient s guardians provided informed consent to while others develop it within a few weeks of diagnosis.3 Bone this study in accordance with the Declaration of Helsinki. DNA and RNA were extracted using standard methods from on marrow aspirate typically reveals varying degrees of abnormal 09/01/2020 myelo- or megakaryopoiesis but must display fewer than 20% buccal and bone marrow mononuclear cells. RNASeq and whole genome sequencing were performed. For additional details, see Supplemental Methods, Supplemental Digital Received for publication May 11, 2020; accepted June 28, 2020. Content 1 (http://links.lww.com/JPHO/A394). From the *Department of Pediatrics, Benioff Children’s Hospital; †Helen Diller Comprehensive Cancer Center, University of RESULTS California San Francisco, San Francisco; and ‡Department of Pediatric Subspecialty, Kaiser Permanente, Oakland, CA. The patient was treated with fludarabine and cytarabine to Supported by the Frank A. Campini Foundation (E.S.) and the German reduce her disease burden before HCT.7 After 1 cycle of che- Cancer Aid (A.B.). The authors declare no conflict of interest. motherapy, the NRAS mutation was no longer detectable and Reprints: Elliot Stieglitz, MD, UCSF, Stieglitz Lab 1450 3rd St, Box 3112, cytogenetic analysis was normal. However, flow cytometry San Francisco, CA 94158 (e-mail: [email protected]). revealed a CD34+ myeloblast population of ∼0.5% with a subset Supplemental Digital Content is available for this article. Direct URL showing immunophenotypic abnormalities with dim partial citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.jpho- CD7 and CD15 expression and moderate to bright CD123 online.com. expression. After conditioning with busulfan, cyclophosphamide, Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. melphalan, and rabbit antithymocyte globulin,8 she received J Pediatr Hematol Oncol Volume 00, Number 00, ’’ 2020 www.jpho-online.com | 1 Copyright r 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Behnert et al J Pediatr Hematol Oncol Volume 00, Number 00, ’’ 2020 AB MWM1 2 574 bp FIGURE 1. A, Reverse transcription polymerase chain reaction (RT-PCR) product of ∼574 base pair on 1.5% agarose gel (MWM, molecular weight marker; lane 1: 15 µL of RT-PCR product loaded; lane 2: 5 µL of RT-PCR product loaded). B, Schematic illustration of NUP98-NSD1 fusion. allogeneic HCT from a 12/12 human leukocyte antigen-matched Whole genome sequencing from diagnosis also confirmed the unrelated donor. Shortly after HCT, research-grade RNA presence of the NRAS mutation and absence of a FLT3-ITD but sequencing using diagnostic material returned, demonstrating a did not reveal any additional mutations. Clinical-grade RT-PCR NUP98-NSD1 gene fusion. Direct sequence analysis revealed an wasthenusedtoconfirm the NUP98-NSD1 fusion using diag- in-frame gene fusion between the NUP98 gene on exon 12 nostic material which allowed for posttransplant monitoring of (chr11:3744509) and NSD1 on exon 6 (chr5:177235821) transcript levels. (Fig. 1B). Reverse transcription polymerase chain reaction The patient’s treatment course was complicated by (RT-PCR)wasusedtovalidatethisfinding using primers veno-occlusive disease and transplant-associated thrombotic flanking NUP98 and NSD1 genes, resulting in a band of ∼574 microangiopathy, which were successfully treated with base pairs (Fig. 1A). The expected sequence was confirmed by defibrotide and eculizumab. The patient is currently alive Sanger sequencing. Principal component analysis of RNASeq and well with absence of NUP98-NSD1 fusion expression by data from patients with JMML, AML, and acute lymphoblastic RT-PCR 5 months after HCT (Fig. 3). However, the patient leukemia showed that this patient clustered closer to other continues to evidence mixed chimerism in her CD3+ cells patients with AML comparedtothosewithJMML(Fig.2). despite rapid taper of tacrolimus. In an effort to achieve full 30 20 UPN3111 10 Disease acute lymphoblastic leukemia acute myeloid leukemia juvenile myelomonocytic leukemia Dim2 (7.2%) 0 −10 −20 −20 −10 0 10 20 Dim1 (11.5%) FIGURE 2. Principal component analysis of RNASeq data from patients with acute lymphoblastic leukemia (n = 878, highlighted in red), patients with acute myeloid leukemia (n = 538, highlighted in yellow), and patients with juvenile myelomonocytic leukemia (n = 20, highlighted in blue). Our patient with NUP98-NSD1 MDS/MPN is indicated by a black arrow. 2 | www.jpho-online.com Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2020 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. J Pediatr Hematol Oncol Volume 00, Number 00, ’’ 2020 NUP98-NSD1 Fusion in Pediatric MDS/MPN AZA AZA + + DLI DLI DLI DLI Flu/Ara-C Days relative to HCT Diagnosis -20HCT +30 +90 +150 +180 Blasts by flow cytometry 5.0% 1.8% 0.0% 0.0% 0.0% 0.0% NRAS MAF 8% 0% 0% n/a n/a n/a Relative NUP98-NSD1 expression 100% n/a 0%* 0%* 0%* 0%* Donor chimerism CD33+ n/a n/a 99% 97% 99% 99% Donor chimerism CD3+ n/a n/a 56% 76% 82% 98% FIGURE 3. Schematic timeline of patient’s clinical course. Timepoints shown are relative to HCT. *NUP98-NSD1
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