Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia
Although aplastic anemia is responsive to immunosuppressive therapy, small subpopulations of hematopoietic cells with clonal gene mutations may exist, and different sets of mutations show distinct clinical behavior and response to therapy. Acquired aplastic anemia is caused by immune-mediated destru...
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| Published in | The New England journal of medicine Vol. 373; no. 1; pp. 35 - 47 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Massachusetts Medical Society
02.07.2015
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| Subjects | |
| Online Access | Get full text |
| ISSN | 0028-4793 1533-4406 1533-4406 |
| DOI | 10.1056/NEJMoa1414799 |
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| Abstract | Although aplastic anemia is responsive to immunosuppressive therapy, small subpopulations of hematopoietic cells with clonal gene mutations may exist, and different sets of mutations show distinct clinical behavior and response to therapy.
Acquired aplastic anemia is caused by immune-mediated destruction of hematopoietic stem and progenitor cells.
1
CD34+ cells and early progenitors are uniformly reduced in aplastic anemia.
2
Bone marrow transplantation is curative, and patients may also have a response to immunosuppressive therapy.
3
,
4
With improved survival, the late development of myelodysplastic syndromes, acute myeloid leukemia (AML), or both has been noted in about 15% of patients and termed “clonal evolution.”
5
Although “clonal evolution” historically has been used to describe the development of cancer in patients with an immune disease, this term is a misnomer, since there is evidence of clonal hematopoiesis associated . . . |
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| AbstractList | Although aplastic anemia is responsive to immunosuppressive therapy, small subpopulations of hematopoietic cells with clonal gene mutations may exist, and different sets of mutations show distinct clinical behavior and response to therapy.
Acquired aplastic anemia is caused by immune-mediated destruction of hematopoietic stem and progenitor cells.
1
CD34+ cells and early progenitors are uniformly reduced in aplastic anemia.
2
Bone marrow transplantation is curative, and patients may also have a response to immunosuppressive therapy.
3
,
4
With improved survival, the late development of myelodysplastic syndromes, acute myeloid leukemia (AML), or both has been noted in about 15% of patients and termed “clonal evolution.”
5
Although “clonal evolution” historically has been used to describe the development of cancer in patients with an immune disease, this term is a misnomer, since there is evidence of clonal hematopoiesis associated . . . In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia. We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients. Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients. Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.). BACKGROUNDIn patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia.METHODSWe performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients.RESULTSSomatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients.CONCLUSIONSClonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.). |
| Author | Hosokawa, Kohei Shiraishi, Yuichi Chiba, Kenichi Wu, Colin O Sanada, Masashi Ogawa, Seishi Scheinberg, Phillip Makishima, Hideki Yoshizato, Tetsuichi Katagiri, Takamasa Tanaka, Hiroko Miyano, Satoru Sato-Otsubo, Aiko Okuno, Yusuke Maciejewski, Jaroslaw P Liu, Delong Clemente, Michael J Kataoka, Keisuke Nagata, Yasunobu Sato, Yusuke Shiozawa, Yusuke Young, Neal S Nakao, Shinji Yoshida, Kenichi Townsley, Danielle Dumitriu, Bogdan Kon, Ayana Suzuki, Hiromichi |
| AuthorAffiliation | 1 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Kyoto-shi Sakyo-ku, Kyoto, 606-8501, Japan 2 Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, United States 6 Laboratory of DNA Information Analysis, Human Genome Center, University of Tokyo, Japan 4 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, United States 5 Office of Biostatistics Research, National Heart, Lung and Blood Institute, Bethesda, United Sates 7 Department of Pediatrics, Graduate School of Medicine, Nagoya University, Japan 3 Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan |
| AuthorAffiliation_xml | – name: 3 Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan – name: 1 Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Kyoto-shi Sakyo-ku, Kyoto, 606-8501, Japan – name: 2 Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, United States – name: 6 Laboratory of DNA Information Analysis, Human Genome Center, University of Tokyo, Japan – name: 7 Department of Pediatrics, Graduate School of Medicine, Nagoya University, Japan – name: 4 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, United States – name: 5 Office of Biostatistics Research, National Heart, Lung and Blood Institute, Bethesda, United Sates |
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Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 3 givenname: Kohei surname: Hosokawa fullname: Hosokawa, Kohei organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. 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Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 5 givenname: Kenichi surname: Yoshida fullname: Yoshida, Kenichi organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. 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Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 7 givenname: Aiko surname: Sato-Otsubo fullname: Sato-Otsubo, Aiko organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. 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Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 12 givenname: Yuichi surname: Shiraishi fullname: Shiraishi, Yuichi organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. 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Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 15 givenname: Yusuke surname: Shiozawa fullname: Shiozawa, Yusuke organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 16 givenname: Yusuke surname: Okuno fullname: Okuno, Yusuke organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 17 givenname: Kenichi surname: Chiba fullname: Chiba, Kenichi organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 18 givenname: Hiroko surname: Tanaka fullname: Tanaka, Hiroko organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 19 givenname: Yasunobu surname: Nagata fullname: Nagata, Yasunobu organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 20 givenname: Takamasa surname: Katagiri fullname: Katagiri, Takamasa organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 21 givenname: Ayana surname: Kon fullname: Kon, Ayana organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 22 givenname: Masashi surname: Sanada fullname: Sanada, Masashi organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 23 givenname: Phillip surname: Scheinberg fullname: Scheinberg, Phillip organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 24 givenname: Satoru surname: Miyano fullname: Miyano, Satoru organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 25 givenname: Jaroslaw P surname: Maciejewski fullname: Maciejewski, Jaroslaw P organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 26 givenname: Shinji surname: Nakao fullname: Nakao, Shinji organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 27 givenname: Neal S surname: Young fullname: Young, Neal S organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) – sequence: 28 givenname: Seishi surname: Ogawa fullname: Ogawa, Seishi organization: From the Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto (T.Y., K.Y., A.S.-O., Y. Sato, H.S., K.K., Y. Shiozawa, Y.N., A.K., M.S., S.O.), Department of Cellular Transplantation Biology, Division of Cancer Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa (K.H., T.K., S.N.), Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo (Y. Shiraishi, K.C., H.T., S.M.), and the Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya (Y.O.) — all in Japan; the Hematology Branch (B.D., K.H., D.T., D.L., P.S., N.S.Y.) and Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, Bethesda, MD; and the Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland (H.M., M.J.C., J.P.M.) |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26132940$$D View this record in MEDLINE/PubMed |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 N.S.Y., and S.O. designed the study. B.D., K.H., T.K., M.C. and H.M. gathered the data. Experiments and data analysis were performed by T.Y., B.D., K.H., H.M., K.Y., A.S., D.L., C.W., K.K., Y. Sato, H.S., Y.N., Y. Shiozawa, T.K., A.K., M.C., M.S., J.M. S.N. and N.S.Y.. Specimens were provided by K.H., H.M., T.K. and M.C.. Bioinfomatical calculations were done by T.Y., D.L., C.W., A.S., Y. Sato, H.S., K.C., Y.O., H.T., Y. Shiozawa, Y. Shiraishi and S.M.. T.Y., P.S., B.D., N.S.Y., and S.O. wrote the first daft and revised the manuscript. N.S.Y. and S.O. are responsible for all the data and analyses and decided to publish the paper. Shared first or last author Author contributions |
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| Snippet | Although aplastic anemia is responsive to immunosuppressive therapy, small subpopulations of hematopoietic cells with clonal gene mutations may exist, and... In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to... BackgroundIn patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to... BACKGROUNDIn patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to... |
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| SubjectTerms | Acute myeloid leukemia Age Age Factors Aged Anemia Anemia, Aplastic - blood Anemia, Aplastic - genetics Anemia, Aplastic - mortality Aplastic anemia Bone marrow Cancer Clone Cells Erythrocytes Female Gene frequency Hematopoiesis - genetics Humans Immune system Immunosuppressive agents Karyotyping Leukemia, Myeloid, Acute - genetics Male Middle Aged Mutation Myelodysplastic syndrome Myelodysplastic Syndromes - genetics Myeloid leukemia Pancytopenia Polymorphism, Single Nucleotide Risk Factors Sequence Analysis, DNA |
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| Title | Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia |
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