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‘CHIP’ping away at clonal hematopoiesis

Leukemia volume 30, pages 1633–1635 (2016)Cite this article

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There is emerging evidence that treatment with myeloablative chemotherapy provides a competitive fitness advantage to HSPCs carrying certain CHIP-associated mutations. We observed that TP53 mutations present in the dominant clone at the time of therapy-related AML (t-AML) diagnosis were detectable at extremely low levels in hematopoietic cells years before cytotoxic chemotherapy exposure.12 This suggests that TP53 mutant cells may be relatively resistant to chemotherapy compared with non-mutant cells (Figure 2). Indeed, we showed that Tp53 mutant cells expand relative to wild-type cells following cytotoxic chemotherapy exposure using an in vivo mouse model.12 The data suggests that rare HSPCs carrying age-related TP53 mutations are resistant to chemotherapy and expand preferentially after treatment. Similarly, our group recently reported the preferential expansion of clonal hematopoietic cells following induction chemotherapy for AML (that is, ‘rising clones’).13 These non-leukemic hematopoietic cells harbored mutations commonly associated with CHIP that were not present in the AML cells, indicating that these mutations identify distinct non-leukemic cells that are different from ‘pre-leukemic’ cells that can persist during AML remission.14, 15

A recent study showed that clonal hematopoiesis is present in nearly half of the patients with aplastic anemia (AA).16 Although there are some notable differences, the spectrum of gene mutations found in AA is similar to that observed in CHIP arising in healthy individuals (Figure 1). This observation raises the possibility that immune-mediated destruction of HSPCs in AA (that is, autoimmunity) could favor expansion of HSCPs carrying CHIP-associated gene mutations (Figure 2). Collectively, these observations suggest that HSPC-extrinsic factors (for example, chemotherapy and autoimmunity) may provide a selective pressure that is conducive for expansion of cells harboring CHIP mutations. Is it possible that additional cell-extrinsic factors affect expansion of mutant cells? We speculate that repeated cycles of infection, systemic inflammation or environmental exposures could transiently alter the bone marrow microenvironment and confer a competitive fitness advantage to HPSCs harboring CHIP mutations—or transiently affect the size of the functional HSPC pool—and allow for periodic waves of clonal expansion of mutant cells leading to CHIP development and ultimately drive disease progression (Figure 2). For example, mutant HSPCs may be more resistant to the inhibitory effects of certain inflammatory cytokines, such as tumor necrosis factor or transforming growth factor-β.17, 18 Although the experimental evidence to support this is lacking, it is testable in model organisms.

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References

  • Welch JS, Ley TJ, Link DC, Miller CA, Larson DE, Koboldt DC et al. The origin and evolution of mutations in acute myeloid leukemia. Cell 2012; 150: 264–278.

    Article  CAS  Google Scholar 

  • Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2015; 126: 9–16.

    Article  CAS  Google Scholar 

  • Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 2012; 44: 1179–1181.

    Article  CAS  Google Scholar 

  • Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 20: 1472–1478.

    Article  CAS  Google Scholar 

  • Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371: 2488–2498.

    Article  Google Scholar 

  • Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014; 371: 2477–2487.

    Article  Google Scholar 

  • McKerrell T, Park N, Moreno T, Grove CS, Ponstingl H, Stephens J et al. Leukemia-associated somatic mutations drive distinct patterns of age-related clonal hemopoiesis. Cell Rep 2015; 10: 1239–1245.

    Article  CAS  Google Scholar 

  • Walter MJ, Shen D, Shao J, Ding L, White BS, Kandoth C et al. Clonal diversity of recurrently mutated genes in myelodysplastic syndromes. Leukemia 2013; 27: 1275–1282.

    Article  CAS  Google Scholar 

  • Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G et al. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 2014; 28: 241–247.

    Article  CAS  Google Scholar 

  • Papaemmanuil E, Gerstung M, Malcovati L, Tauro S, Gundem G, Van Loo P et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 2013; 122: 3616–3627.

    Article  CAS  Google Scholar 

  • Research TCGA. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013; 368: 2059–2074.

    Article  Google Scholar 

  • Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature 2015; 518: 552–555.

    Article  CAS  Google Scholar 

  • Wong TN, Miller CA, Klco JM, Petti A, Demeter R, Helton NM et al. Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML. Blood 2016; 127: 893–897.

    Article  CAS  Google Scholar 

  • Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014; 506: 328–333.

    Article  CAS  Google Scholar 

  • Jan M, Snyder TM, Corces-Zimmerman MR, Vyas P, Weissman IL, Quake SR et al. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia. Sci Transl Med 2012; 4: 149ra118.

    Article  Google Scholar 

  • Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D et al. Somatic mutations and clonal hematopoiesis in Aplastic Anemia. N Engl J Med 2015; 373: 35–47.

    Article  CAS  Google Scholar 

  • Fleischman AG, Aichberger KJ, Luty SB, Bumm TG, Petersen CL, Doratotaj S et al. TNFalpha facilitates clonal expansion of JAK2V617F positive cells in myeloproliferative neoplasms. Blood 2011; 118: 6392–6398.

    Article  CAS  Google Scholar 

  • Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H, Shioda S et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 2011; 147: 1146–1158.

    Article  CAS  Google Scholar 

  • Lindsley RC, Mar BG, Mazzola E, Grauman PV, Shareef S, Allen SL et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015; 125: 1367–1376.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by a Leukemia and Lymphoma Society Scholar Award (MJW). We are grateful to Tim Ley for helpful scientific discussions.

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  1. Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA

    D C Link & M J Walter

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Correspondence to M J Walter.

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Link, D., Walter, M. ‘CHIP’ping away at clonal hematopoiesis. Leukemia 30, 1633–1635 (2016). https://doi.org/10.1038/leu.2016.130

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