ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF
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ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF. / Triviai, Ioanna; Zeschke, Silke; Rentel, Jan; Spanakis, Marios; Scherer, Theo; Gabdoulline, Razif; Panagiota, Victoria; Thol, Felicitas; Heuser, Michael; Stocking, Carol; Kröger, Nicolaus.
In: LEUKEMIA, Vol. 33, No. 1, 01.2019, p. 99-109.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF
AU - Triviai, Ioanna
AU - Zeschke, Silke
AU - Rentel, Jan
AU - Spanakis, Marios
AU - Scherer, Theo
AU - Gabdoulline, Razif
AU - Panagiota, Victoria
AU - Thol, Felicitas
AU - Heuser, Michael
AU - Stocking, Carol
AU - Kröger, Nicolaus
PY - 2019/1
Y1 - 2019/1
N2 - Primary myelofibrosis (PMF) is a hematopoietic stem cell (HSC) disease, characterized by aberrant differentiation of all myeloid lineages and profound disruption of the bone marrow niche. PMF samples carry several mutations, but their cell origin and hierarchy in regulating the different waves of clonal and aberrant myeloproliferation from the prime HSC compartment is poorly understood. Genotyping of >2000 colonies from CD133+HSC and progenitors from PMF patients confirmed the complex genetic heterogeneity within the neoplastic population. Notably, mutations in chromatin regulators ASXL1 and/or EZH2 were identified as the first genetic lesions, preceding both JAK2-V617F and CALR mutations, and are thus drivers of clonal myelopoiesis in a PMF subset. HSC from PMF patients with double ASXL1/EZH2 mutations exhibited significantly higher engraftment in immunodeficient mice than those from patients without histone modifier mutations. EZH2 mutations correlate with aberrant erythropoiesis in PMF patients, exemplified by impaired maturation and cell cycle arrest of erythroid progenitors. These data underscore the importance of post-transcriptional modifiers of histones in neoplastic stem cells, whose clonal growth sustains aberrant myelopoiesis and expansion of pre-leukemic clones in PMF.
AB - Primary myelofibrosis (PMF) is a hematopoietic stem cell (HSC) disease, characterized by aberrant differentiation of all myeloid lineages and profound disruption of the bone marrow niche. PMF samples carry several mutations, but their cell origin and hierarchy in regulating the different waves of clonal and aberrant myeloproliferation from the prime HSC compartment is poorly understood. Genotyping of >2000 colonies from CD133+HSC and progenitors from PMF patients confirmed the complex genetic heterogeneity within the neoplastic population. Notably, mutations in chromatin regulators ASXL1 and/or EZH2 were identified as the first genetic lesions, preceding both JAK2-V617F and CALR mutations, and are thus drivers of clonal myelopoiesis in a PMF subset. HSC from PMF patients with double ASXL1/EZH2 mutations exhibited significantly higher engraftment in immunodeficient mice than those from patients without histone modifier mutations. EZH2 mutations correlate with aberrant erythropoiesis in PMF patients, exemplified by impaired maturation and cell cycle arrest of erythroid progenitors. These data underscore the importance of post-transcriptional modifiers of histones in neoplastic stem cells, whose clonal growth sustains aberrant myelopoiesis and expansion of pre-leukemic clones in PMF.
KW - Journal Article
UR - https://www.nature.com/articles/s41375-018-0159-0.epdf?author_access_token=eUHhQ_hXkWcEtrOONoD9NtRgN0jAjWel9jnR3ZoTv0Opcw9HV32FfCG8LOXU3mC5ERVQ_yU9QqSTxPA_obaIocBHX8p33A-9SXTxQn5K5WbgO6cjsUVWzLFmLBE7WeVPkFJi13s0BzqmV62XEvNTmQ%3D%3D
U2 - 10.1038/s41375-018-0159-0
DO - 10.1038/s41375-018-0159-0
M3 - SCORING: Journal article
C2 - 29907810
VL - 33
SP - 99
EP - 109
JO - LEUKEMIA
JF - LEUKEMIA
SN - 0887-6924
IS - 1
ER -