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Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis

Item Type:Article
Title:Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis
Creators Name:Arends, C.M. and Galan-Sousa, J. and Hoyer, K. and Chan, W. and Jäger, M. and Yoshida, K. and Seemann, R. and Noerenberg, D. and Waldhueter, N. and Fleischer-Notter, H. and Christen, F. and Schmitt, C.A. and Dörken, B. and Pelzer, U. and Sinn, M. and Zemojtel, T. and Ogawa, S. and Märdian, S. and Schreiber, A. and Kunitz, A. and Krüger, U. and Bullinger, L. and Mylonas, E. and Frick, M. and Damm, F.
Abstract:Clonal hematopoiesis of indeterminate potential (CHIP) occurs in an age-related manner and associates with an increased risk of hematologic cancer, atherosclerotic disease, and shorter overall survival. Little is known about the cell of origin, repartition patterns of clonal mutations within the hematopoietic differentiation tree, and its dynamics under evolutionary pressure. Using targeted sequencing, CHIP was identified in 121 out of 437 elderly individuals (27.7%). Variant allele frequencies (VAFs) of 91 mutations were studied in six peripheral blood cell fractions. VAFs were significantly higher in monocytes, granulocytes, and NK-cells compared to B- or T cells. In all cases with available bone marrow material, mutations could be identified in LinCD34CD38HSCs with subsequent expansion to myeloid primed progenitors. In 22 patients with solid cancer receiving (radio-)chemotherapy, longitudinal study of 32 mutations at 121 time points identified relative VAF changes of at least 50% in 13/32 mutations. VAFs of DNMT3A, were stable in 12/13 cases (P < .001). Cancer patients with a clonal mutation other than DNMT3A required more often red blood cell transfusions and dose reductions. Our results provide novel insights into cellular distribution of clonal mutations, their dynamics under chemotherapy, and advocate for systematic analyses for CHIP in cancer patients.
Source:Leukemia
ISSN:0887-6924
Publisher:Nature Publishing Group (U.K.)
Volume:32
Number:9
Page Range:1908-1919
Date:September 2018
Official Publication:https://doi.org/10.1038/s41375-018-0047-7
PubMed:View item in PubMed

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