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Stem cell biology

Clonal hematopoiesis by SLIT1-mutated hematopoietic stem cells due to a breakdown of the autocrine loop involving Slit1 in acquired aplastic anemia

Leukemia volume 33, pages 2732–2766 (2019)Cite this article

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Acquired aplastic anemia (AA) is a hematopoietic disorder caused by an immune attack on hematopoietic stem and progenitor cells (HSPCs) and has been thought to be rarely associated with the acquired genetic defects in HSPCs. However, recent studies have found that clonal hematopoiesis from HSPCs with genetic alterations is not so uncommon in AA [1]. For instance, clonal granulocyte populations of the paroxysmal nocturnal hemoglobinuria (PNH) phenotype and uniparental disomy of chromosome 6p are detected in 50 and 13% patients with AA, respectively [2, 3], and represent the immune pathophysiology of bone marrow (BM) failure. Given that even a chromosomal abnormality like del(13q) is associated with good response to immunosuppressive therapy (IST) [4], hematopoiesis in AA patients in remission after IST is likely supported by a limited number of HSPCs, with acquired genetic changes that survived the attack on the immune system. At present, however, how these mutant HSPCs contribute to hematopoiesis in AA patients remains largely unknown.

Slit1 is a member of the Slit family that binds to members of the Robo receptor family [5]. The interaction between Slit and Robo inhibits leukocyte chemotaxis, migration, and proliferation, and induces apoptosis in normal and tumor cells [6]. Some studies have found that the Slit/Robo pathway regulates cell function in both an autocrine and paracrine manner [7, 8]. However, little is known about the role of this pathway in the regulation of hematopoiesis. We detected clonal hematopoiesis by HSPCs with SLIT1 mutations in two patients with acquired AA, who were in remission after IST. Since Slit1 negatively regulates various cell types, mutations in Slit1 could represent a novel mechanism underlying “benign” clonal hematopoiesis in patients with immune-mediated BM failure. To test this hypothesis, we investigated the mechanism underlying clonal hematopoiesis, using a mutant Slit1 protein that harbors a mutation identified in one of the AA patients.

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Acknowledgements

The authors thank Rie Ohmi (Kanazawa University) and Naoya Hosono (Fluidigm Corporation) for their excellent technical assistance. Wild-type Slit1 vector (pENTR2B-hSlit1) was a gift from Professor Kazunobu Sawamoto from Nagoya City University Graduate School of Medical Sciences. This study was supported by a MEXT Grant-in-Aid for Scientific Research (B, 24390243 to SN and Young Scientists (B), 17K16184 to KH).

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  1. These authors contributed equally: Kohei Hosokawa, Hiroki Mizumaki

Authors and Affiliations

  1. Department of Hematology & Respirology, Kanazawa University, Kanazawa, Japan

    Kohei Hosokawa, Hiroki Mizumaki, Mahmoud I. Elbadry, Chizuru Saito, J. Luis Espinoza, An Thi Thanh Dao & Shinji Nakao

  2. Pediatric Department, University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam

    An Thi Thanh Dao

  3. Department of Clinical Laboratory Sciences, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan

    Takamasa Katagiri

  4. Department of Biochemistry, Kanazawa University, Kanazawa, Japan

    Ai Harashima & Yasuhiko Yamamoto

  5. Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

    Akihiro Kikuchi

  6. Division of Endocrinology and Metabolism, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki, Japan

    Akihiro Kikuchi

  7. Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Akinori Kanai, Hirotaka Matsui & Toshiya Inaba

  8. Department of Hematology, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Masafumi Taniwaki

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  1. Kohei Hosokawa
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Contributions

KH and SN designed the research, analyzed the data, and wrote the paper. KH, HM, ME, CS, LE, AD, TK, AH, AK, AK, HM, TI, MT and YY performed the experiments. SN was involved in the conceptualization, interpretation of the results, and editing of the paper. All authors critically reviewed the paper and agree with the submission of the final paper.

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Correspondence to Shinji Nakao.

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Hosokawa, K., Mizumaki, H., Elbadry, M.I. et al. Clonal hematopoiesis by SLIT1-mutated hematopoietic stem cells due to a breakdown of the autocrine loop involving Slit1 in acquired aplastic anemia. Leukemia 33, 2732–2766 (2019). https://doi.org/10.1038/s41375-019-0510-0

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