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2014 Comprehensive Genetic Analysis Revealed Myeloid/Natural Killer (NK) Cell Precursor Acute Leukemia As a Novel Distinctive Leukemia Entity

Program: Oral and Poster Abstracts
Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Leukemia, Diseases, Biological Processes, white blood cells, Cell Lineage, Lymphoid Malignancies, pathogenesis
Sunday, December 6, 2020, 7:00 AM-3:30 PM

Akira Nishimura, MD1*, Kazuaki Yokoyama, MD, PhD2, Chika Yamagishi, MD3*, Toshihiko Imamura, MD, PhD4,5, Takuya Naruto, MD, PhD3*, Tomohiro Morio, MD, PhD3*, Yukie Tanaka, PhD6*, Akinori Kanai, PhD7*, Hirotaka Matsui, MD, PhD8*, Naoko Higuchi, MD9*, Akiko Takada, MD10*, Haruna Okuno, MD11*, Shoji Saito, MD, PhD12, Shuhei Karakawa, MD, PhD13*, Shogo Kobayashi, MD14*, Daisuke Hasegawa, MD, PhD15*, Hiroyuki Fujisaki, MD, PhD16*, Daiichiro Hasegawa, MD, PhD17, Kazutoshi Koike, MD, PhD18*, Takashi Koike, MD19*, Shinya Rai, MD, PhD20*, Katsutsugu Umeda, MD, PhD10*, Hideki Sano, MD14*, Yujin Sekinaka, MD, PhD21, Atsushi Ogawa, MD, PhD22*, Akitoshi Kinoshita, MD, PhD23*, Norio Shiba, MD, PhD24, Mizuka Miki, MD25*, Fumihiko Kimura, MD, PhD26, Hideki Nakayama, MD27*, Yozo Nakazawa, MD, PhD28*, Takashi Taga, MD, PhD5,29*, Tomohiko Taki, MD, PhD5,30, Souichi Adachi, MD, PhD5,31, Atsushi Manabe, MD, PhD5,32, Katsuyoshi Koh, MD5,33*, Yasushi Ishida, MD, PhD5,34*, Arinobu Tojo, MD, PhD35 and Masatoshi Takagi, MD, PhD3,5

1Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, TKY, Japan
2Department of Hematology/Oncology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, TKY, Japan
3Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
4Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan
5Leukemia/Lymphoma Committee of Japanese Society of Pediatric Hematology and Oncology, Tokyo, Japan
6Research Core, Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
7Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
8Department of Molecular Laboratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
9Department of Pediatrics, University of Occupational and Environmental Health, Kitakyushu, Japan
10Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
11Department of Pediatrics, Gunma University Hospital, Maebashi, Japan
12Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, NAG, Japan
13Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan
14Department of Pediatric Oncology, Fukushima Medical University Hospital, Fukushima, Japan
15Department of Pediatrics, St. Luke's International Hospital, Tokyo, JPN
16Department of Pediatric Hematology and Oncology, Osaka City General Hospital, Osaka, Japan
17Department of Hematology and Oncology, Hyogo Prefectural Kobe Children's Hospital, Kobe, Japan
18Division of Pediatric Hematology and Oncology, Ibaraki Children’s Hospital, Mito, Japan
19Department of Pediatrics, Tokai University School of Medicine, Isehara, Japan
20Division of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Osakasayama, Japan
21Department of Pediatrics, National Defense Medical College, Tokorozawa, JPN
22Department of Pediatrics, Niigata Cancer Center Hospital, Niigata, Japan
23Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Japan
24Department of Pediatrics, Yokohama City University, Yokohama, Japan
25Department of Pediatrics, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
26Division of Hematology, Department of Internal Medicine, National Defense Medical College, Tokorozawa, Japan
27Department of Pediatrics, Kyushu Cancer Center, Fukuoka, Japan
28Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
29Department of Pediatrics, Shiga University of Medical Science, Ohtsu, Japan
30Department of Medical Technology, Faculty of Health Sciences, Kyorin University, Tokyo, Japan
31Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
32Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
33Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan
34Pediatric Medical Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
35Division of Molecular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo Japan., Tokyo, Japan

Introduction: Myeloid/Natural killer (NK) cell precursor acute leukemia (MNKPL) is a rare hematologic malignancy prevalent in East Asia. MNKPL is characterized by extramedullary involvement, immature lymphoblastoid morphology without myeloperoxidase (MPO) reactivity, the CD7+/CD33+/CD34+/CD56+/HLA−DR+ phenotype. MNKPL is classified as mixed phenotype acute leukemia, and not otherwise specified rare types (MPAL NOS rare types) in WHO classification. However, its characteristic clinical feature and undetermined genetic feature suggests that MNPKL leaves open the possibility of a new independent disease concept. Here, we report clinical features and genetic alterations in patients with MNKPL.

Methods: The Leukemia and Lymphoma Committee of the Japanese Society of Pediatric Hematology and Oncology (JSPHO) sent out questionnaires to 110 JSPHO affiliated hospitals and collected cases of MNPKL diagnosed during the period 2000–2013. Besides, the cases published as literature were recruited. The data of clinical features, cell surface antigen profiling, overall survival (OS), and event-free survival (EFS) defined as relapse or death were also collected as a secondary survey. The protocol of this retrospective study was approved by the review boards of JSPHO and Ehime Prefectural Central Hospital. Comprehensive genetic analysis including 13 whole-exome sequences (WES), 2 target sequence, 6 RNA sequence (RNA-seq), and 8 DNA methylation analysis was performed. We also performed single-cell RNA-seq using 1 sample of MNKPL patients and a normal bone marrow sample as the reference. The research protocol was approved by the review board of TMDU.

Results: Sixteen children or young adults (< 39 years old) and 2 older adults with MNKPL were identified. The median age of MNKPL patients was 11 (0.5–75) years old. There are 12 males and 6 females. The extramedullary involvement was observed in 7 patients. Complete remission after induction therapy was achieved in 8/14 (57%) patients treated with acute myeloid leukemia (AML) type chemotherapy and 2/4 (50%) patients treated with acute lymphoblastic leukemia (ALL)/non-Hodgkin lymphoma type chemotherapy, respectively. Fifteen patients underwent hematopoietic cell transplantation (HCT). The median follow-up period was 3.8 (0.1–16.0) years. 5-year OS and 5-year EFS was 49.5% and 40.7%, respectively.

In genetic analysis, median 388 somatic mutations in MNKPL were identified by WES. The recurrent mutations were observed in NOTCH1 (n=5), MAML3 (n=4), NRAS, MAP3K4, RECQL4, CREBBP, ASXL2, and KMT2D (n=3, respectively), and MAML2, MAP3K1, FLT3, CARD11, MSH4, FANCI, WT1, ZNF384, and ERG (n=2, respectively). The distinct expression pattern, higher expression of RUNX3 and NOTCH1, and lower expression of BCL11B were identified in MNKPL samples which were compared to MPAL, AML, and T cell ALL in RNA-seq. The distinct methylation profile, hypomethylation of RUNX3 regulatory region, and hypermethylation of BCL11B regulatory region were identified in DNA methylation analysis. Single-cell RNA-seq analysis also showed distinct 4 subsets of MNKPL.

Discussion and Conclusions: NK cells are the founding member of a family of innate lymphoid cells (ILC). Genetic abnormality of NOTCH1 pathway is a hallmark of MNPKL. RUNX3 is required for NK cell survival and proliferation in response to IL-15 signaling. RUNX3 high expression and hypomethylation of RUNX3 regulatory region also characterize MNKPL. Currently, MNKPL is classified as MPAL NOS, our genetic analysis revealed that MNKPL is a distinct group from MPAL. The prognosis of MNKPL was not satisfactory even though HCT was performed. The development of new therapeutic approaches based on these genetic analyses is highly expected.

Disclosures: Saito: Toshiba Corporation: Research Funding. Nakazawa: Toshiba Corporation: Research Funding.

*signifies non-member of ASH