Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis
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Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis. / Arends, Christopher Maximilian; Galan-Sousa, Joel; Hoyer, Kaja; Chan, Willy; Jäger, Marten; Yoshida, Kenichi; Seemann, Ricarda; Noerenberg, Daniel; Waldhueter, Nils; Fleischer-Notter, Helga; Christen, Friederike; Schmitt, Clemens A; Dörken, Bernd; Pelzer, Uwe; Sinn, Marianne; Zemojtel, Tomasz; Ogawa, Seishi; Märdian, Sven; Schreiber, Adrian; Kunitz, Annegret; Krüger, Ulrike; Bullinger, Lars; Mylonas, Elena; Frick, Mareike; Damm, Frederik.
In: LEUKEMIA, Vol. 32, No. 9, 09.2018, p. 1908-1919.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Hematopoietic lineage distribution and evolutionary dynamics of clonal hematopoiesis
AU - Arends, Christopher Maximilian
AU - Galan-Sousa, Joel
AU - Hoyer, Kaja
AU - Chan, Willy
AU - Jäger, Marten
AU - Yoshida, Kenichi
AU - Seemann, Ricarda
AU - Noerenberg, Daniel
AU - Waldhueter, Nils
AU - Fleischer-Notter, Helga
AU - Christen, Friederike
AU - Schmitt, Clemens A
AU - Dörken, Bernd
AU - Pelzer, Uwe
AU - Sinn, Marianne
AU - Zemojtel, Tomasz
AU - Ogawa, Seishi
AU - Märdian, Sven
AU - Schreiber, Adrian
AU - Kunitz, Annegret
AU - Krüger, Ulrike
AU - Bullinger, Lars
AU - Mylonas, Elena
AU - Frick, Mareike
AU - Damm, Frederik
PY - 2018/9
Y1 - 2018/9
N2 - 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 Lin-CD34+CD38- HSCs 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.
AB - 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 Lin-CD34+CD38- HSCs 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.
KW - Age Factors
KW - Aged
KW - Aged, 80 and over
KW - Alleles
KW - Biomarkers
KW - Cell Differentiation
KW - Clonal Evolution
KW - DNA Mutational Analysis
KW - Female
KW - Gene Frequency
KW - Hematopoiesis
KW - Hematopoietic Stem Cells/cytology
KW - Humans
KW - Immunophenotyping
KW - Male
KW - Middle Aged
KW - Mutation
KW - Polymorphism, Single Nucleotide
U2 - 10.1038/s41375-018-0047-7
DO - 10.1038/s41375-018-0047-7
M3 - SCORING: Journal article
C2 - 29491455
VL - 32
SP - 1908
EP - 1919
JO - LEUKEMIA
JF - LEUKEMIA
SN - 0887-6924
IS - 9
ER -