Mutant ASXL1 exacerbates CALR-mutant myeloproliferative neoplasms by enhancing a distinct megakaryocyte differentiation program
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
- Maximilian Englert (ORCID: https://orcid.org/0000-0002-9066-5801)
- Jessica W. Hem
- Anna E. Marneth (ORCID: https://orcid.org/0000-0001-9065-0581)
- Malvina Papanastasiou (ORCID: https://orcid.org/0000-0003-3378-6612)
- Andrew H. Reiter (ORCID: https://orcid.org/0000-0003-1406-4913)
- Ann Mullally (ORCID: https://orcid.org/0000-0001-9727-8495)
- F. Kramer (ORCID: https://orcid.org/0000-0002-7615-9291)
- Steven A. Carr (ORCID: https://orcid.org/0000-0002-7203-4299)
- Raghda Fouda (ORCID: https://orcid.org/0000-0001-6436-6093)
- Christian Hackenbroch (ORCID: https://orcid.org/0000-0003-4148-5035)
- Xintao Qiu (ORCID: https://orcid.org/0000-0002-8560-7017)
- Benjamin Rolles (ORCID: https://orcid.org/0000-0002-7393-861X)
- Tsega‐Ab Abera
- Rong Li (ORCID: https://orcid.org/0000-0002-6476-1015)
- Masashi Miyauchi (ORCID: https://orcid.org/0000-0002-6301-3429)
- Anna S. Nam (ORCID: https://orcid.org/0000-0003-4192-8916)
- Mifra Faiz (ORCID: https://orcid.org/0000-0001-8681-6286)
- Olga Pozdnyakova (ORCID: https://orcid.org/0000-0003-3529-5622)
- Merle Riedemann (ORCID: https://orcid.org/0009-0004-5457-7451)
- Adela Herce
- Gabriela S. Hobbs
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Stanford Medicine (US)
- Weill Cornell Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-10-29
- DOI
- https://doi.org/10.1172/jci201732
- Primary Topic
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00