ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF

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 -