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ResearchIn-Press PreviewHematologyOncology Open Access | 10.1172/JCI201732

Mutant ASXL1 exacerbates CALR-mutant myeloproliferative neoplasms by enhancing a distinct megakaryocyte differentiation program

Frederike Kramer,1 Merle Riedemann,1 Tsega-Ab Abera,2 Jessica Hem,1 Adela Herce,1 Anna E. Marneth,1 Benjamin Rolles,1 Maximilian Englert,3 Christian Hackenbroch,3 Mifra Faiz,1 Malvina Papanastasiou,4 Andrew H. Reiter,4 Steven A. Carr,4 Rong Li,5 Xintao Qiu,5 Gabriela S. Hobbs,6 Raghda Fouda,3 Olga Pozdnyakova,7 Masashi Miyauchi,3 Anna S. Nam,2 and Ann Mullally3

1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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1Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, United States of America

3Division of Hematology, Department of Medicine, Stanford University School of Medicine, Stanford, United States of America

4The Broad Institute of MIT and Harvard, Cambridge, United States of America

5Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, United States of America

6Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, United States of America

7Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States of America

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Published October 29, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI201732.
Copyright © 2026, Kramer et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 29, 2026 - Version history
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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.

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  • Version 1 (October 29, 2026): In-Press Preview
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