Abstract
ASXL1 mutations confer a poor prognosis in myeloid neoplasms, including in CALR-mutated myeloproliferative neoplasms (MPN). We generated Calr-Asxl1 co-mutant mice and found more severe thrombocytosis and increased splenomegaly, compared with Calr single-mutant animals. Calr-Asxl1 co-mutant megakaryocytes displayed more pronounced morphological abnormalities and enhanced emperipolesis characteristic of inflammation. Concordant with this, a differentiation trajectory directly to megakaryocytes from hematopoietic stem cells (HSC) was more prominent in Calr-Asxl1 co-mutant mice. In this non-canonical trajectory, where megakaryocyte-biased HSCs directly differentiate into megakaryocyte progenitors, we found upregulation of Mef2c, a key transcriptional regulator of megakaryocyte lineage commitment. Mature Calr-Asxl1 co-mutant megakaryocytes displayed an enhanced proinflammatory transcriptional state, whereas the transcriptional signature of Calr-Asxl1 co-mutant HSCs was indicative of inflammation-resistance. Genotyping of transcriptomes (GoT) confirmed an activated megakaryocytic differentiation program in CALR-ASXL1 co-mutant HSCs in primary human MPN bone marrow. These findings link the enhanced severity of CALR-ASXL1 co-mutant MPN to altered megakaryocyte differentiation and help explain some of the biological basis for the more severe MPN phenotype observed in patients.
Authors
Frederike Kramer, Merle Riedemann, Tsega-Ab Abera, Jessica Hem, Adela Herce, Anna E. Marneth, Benjamin Rolles, Maximilian Englert, Christian Hackenbroch, Mifra Faiz, Malvina Papanastasiou, Andrew H. Reiter, Steven A. Carr, Rong Li, Xintao Qiu, Gabriela S. Hobbs, Raghda Fouda, Olga Pozdnyakova, Masashi Miyauchi, Anna S. Nam, Ann Mullally
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ISSN: 0021-9738 (print), 1558-8238 (online)