Abstract
In acute myeloid leukemia (AML), patients may harbor pre-leukemic hematopoietic stem cells (HSCs) containing some, but not all, of the mutations observed in the leukemic cells. These pre-leukemic HSCs may survive induction chemotherapy and contribute to AML relapse by obtaining additional mutations. We report here an acute monoblastic leukemia (AMoL) patient who later developed an unclassifiable myeloproliferative neoplasm (MPN-U). Whole-exome sequencing and cluster analysis demonstrated the presence of three distinct major clones during the clinical course: (1) an AMoL clone with ASXL1, CBL, and NPM1 somatic mutations, likely associated with the pathogenesis, and GATA2, SRSF2, and TET2 mutations, (2) an AMoL remission clone, with mutated GATA2, SRSF2, and TET2 only (possibly the founding clone (pre-leukemic HSC) that survived chemotherapy), (3) a small subclone which had JAK2 mutation during the AMoL remission, appearing at MPN-U manifestation with additional mutations. These findings suggest that pre-leukemic HSCs in AML patients may give rise to non-AML myeloid malignancies. This is the first report to analyze the clonal evolution from AMoL to MPN-U, which may provide new insight into the development of myeloid malignancies.
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References
Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, et al. Clonal evolution in relapsed acute myeloid leukemia revealed by whole-genome sequencing. Nature. 2012;481(7382):506–10.
Corces-Zimmerman MR, Hong WJ, Weissman IL, Medeiros BC, Majeti R. Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission. Proc Natl Acad Sci USA. 2014;111(7):2548–53.
Shlush LI, Zandi S, Mitchell A, Chen WC, Brandwein JM, Gupta V, et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukemia. Nature. 2014;506(7488):328–33.
Lundberg P, Karow A, Nienhold R, Looser R, Hao-Shen H, Nissen I, et al. Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. Blood. 2014;123(14):2220–8.
Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379–90.
Nangalia J, Massie CE, Baxter EJ, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369(25):2391–405.
Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360(22):2289–301.
Miller CA, White BS, Dees ND, Griffith M, Welch JS, Griffith OL, et al. SciClone: inferring clonal architecture and tracking the spatial and temporal patterns of tumor evolution. PLoS Comput Biol. 2014;10(8):e1003665.
Malikic S, McPherson AW, Donmez N, Sahinalp CS. Clonality inference in multiple tumor samples using phylogeny. Bioinformatics. 2015;31(9):1349–56.
Stratton MR, Campbell PJ, Futreal PA. The cancer genome. Nature. 2009;458(7239):719–24.
Greaves M, Maley CC. Clonal evolution in cancer. Nature. 2012;481(7381):306–13.
Falini B, Martelli MP, Bolli N, Sportoletti P, Liso A, Tiacci E, et al. Acute myeloid leukemia with mutated nucleophosmin (NPM1): is it a distinct entity? Blood. 2011;117(4):1109–20.
Sportoletti P, Varasano E, Rossi R, Mupo A, Tiacci E, Vassiliou G, et al. Mouse models of NPM1-mutated acute myeloid leukemia: biological and clinical implications. Leukemia. 2015;29(2):269–78.
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(1):9–16.
Kunimoto H, Nakajima H. Epigenetic dysregulation of hematopoietic stem cells and preleukemic state. Int J Hematol. 2017;016(1):34–44.
Abdel-Wahab O, Adli M, LaFave LM, Gao J, Hricik T, Shih AH, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell. 2012;22(2):180–93.
Kohlmann A, Grossmann V, Klein HU, Schindela S, Weiss T, Kazak B, et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol. 2010;28(24):3858–65.
Suzuki T, Kiyoi H, Ozeki K, Tomita A, Yamaji S, Suzuki R, et al. Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. Blood. 2005;106(8):2854–61.
Greif PA, Dufour A, Konstandin NP, Ksienzyk B, Zellmeier E, Tizazu B, et al. GATA2 zinc finger 1 mutations associated with biallelic CEBPA mutations define a unique genetic entity of acute myeloid leukemia. Blood. 2012;120(2):395–403.
Hahn CN, Chong CE, Camichael CL, Wilkins EJ, Brautigan PJ, Li XC, et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet. 2011;43(10):1012–7.
Makishima H, Yoshizato T, Yoshida K, Sekeres MA, Radivoyevitch T, Suzuki H, et al. Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet. 2017;49(2):204–12.
Prick J, de Haan G, Green AR, Kent DG. Clonal heterogeneity as a driver of disease variability in the evolution of myeloproliferative neoplasms. Exp Hematol. 2014;42(10):841–51.
Campbell PJ, Baxter EJ, Beer PA, Scott LM, Bench AJ, Huntly BJ, et al. Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation. Blood. 2006;108(10):3548–55.
Acknowledgements
We would like to thank Ms. N. Shirahama, Ms Y. Urakami, and Ms. C. Hayashida for their assistance.
Funding
This work was supported in part by grant from the Ministry of Health, Labor and Welfare (No. 26271301), Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 26461426) and the Program of the Network-type Joint Usage/Research Centre for Radiation Disaster Medical Science.
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S.S., H.I., K.Y. and Ya.M. designed the research; S.S., H.I., M.T., H.M. and A.K. performed genome analysis under the supervision of K.Y.; S.S., H.I., M.T., Y.S., D.I., H.T., T.H., Yu.M. and Ya.M. made diagnoses and analyzed clinical data; S.S., H.I., M.T., H.T., H.M. and Ya.M. wrote the paper; and all reviewed the manuscript. H.I. and M.T. contributed equally to this study.
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Sato, S., Itonaga, H., Taguchi, M. et al. Clonal dynamics in a case of acute monoblastic leukemia that later developed myeloproliferative neoplasm. Int J Hematol 108, 213–217 (2018). https://doi.org/10.1007/s12185-018-2419-1
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DOI: https://doi.org/10.1007/s12185-018-2419-1