Advertisement

ResearchIn-Press PreviewCell biologyHematology Open Access | 10.1172/JCI189266

Splicing of erythroid transcription factor is associated with therapeutic response in myelodysplastic syndromes

Srinivas Aluri,1 Te Ling,2 Ellen Fraint,3 Samarpana Chakraborty,1 Kevin Zhang,2 Aarif Ahsan,4 Leah Kravets,1 Gowri Poigaialwar,5 Rongbao Zhao,1 Kith Pradhan,1 Anitria Cotton,2 Kimo Bachiashvili,1 Jung-In Yang,1 Anjali Budhathoki,1 Beamon Agarwal,6 Shanisha Gordon-Mitchell,1 Milagros Carbajal,1 Srabani Sahu,1 Jacqueline Boultwood,7 Andrea Pellagatti,7 Ulrich Steidl,5 Amittha Wickrema,8 Satish Nandakumar,5 Aditi Shastri,1 Rajasekhar N.V.S. Suragani,9 Teresa V. Bowman,3 John D. Crispino,2 Sadanand Vodala,4 and Amit Verma1

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Aluri, S. in: PubMed | Google Scholar |

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Ling, T. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Fraint, E. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Chakraborty, S. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Zhang, K. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Ahsan, A. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Kravets, L. in: PubMed | Google Scholar |

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Poigaialwar, G. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Zhao, R. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Pradhan, K. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Cotton, A. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Bachiashvili, K. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Yang, J. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Budhathoki, A. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Agarwal, B. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Gordon-Mitchell, S. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Carbajal, M. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Sahu, S. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Boultwood, J. in: PubMed | Google Scholar |

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Pellagatti, A. in: PubMed | Google Scholar |

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Steidl, U. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Wickrema, A. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Nandakumar, S. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Shastri, A. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Suragani, R. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Bowman, T. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Crispino, J. in: PubMed | Google Scholar |

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Vodala, S. in: PubMed | Google Scholar

1Department of Medicine, Albert Einstein College of Medicine, New York, United States of America

2Department of Hematology, St Jude Children's Research Hospital, Memphis, United States of America

3Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, United States of America

4Bristol Myers Squibb, Summit, United States of America

5Department of Cell Biology, Albert Einstein College of Medicine, New York, United States of America

6Pathology, GenomeRxUS, Secane, United States of America

7Radcliffe Department of Medicine, Oxford University, Oxford, United Kingdom

8Department of Medicine, University of Chicago, Chicago, United States of America

9Hematology Translational Medicine, Bristol Myers Squibb, Summit, United States of America

Find articles by Verma, A. in: PubMed | Google Scholar

Published May 27, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI189266.
Copyright © 2025, Aluri 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 May 27, 2025 - Version history
View PDF
Abstract

Anemia is the primary clinical manifestation of myelodysplastic syndromes (MDS), but the molecular pathogenesis of ineffective erythropoiesis remains incompletely understood. Luspatercept, an activin receptor 2B (ACVRIIB-Fc) ligand trap, has been approved to treat anemia, however its molecular mechanism of action is unclear. We found that the ACVR2B, its ligand GDF11, and effector, SMAD2, are upregulated in MDS patient samples. GDF11 inhibited human erythropoiesis in vitro and caused anemia in zebrafish, effects that were abrogated by luspatercept. Upon GDF11 stimulation of human erythroid progenitors, SMAD2 binding occurred in the erythroid regulatory regions, including at GATA1 intron. Intronic SMAD2 binding led to skipping of exon 2 of GATA1, resulting in a shorter, hypomorphic isoform (GATA1s). CRISPR deletion of the SMAD2 binding intronic region decreased GATA1s production upon GDF11 stimulation. Expression of gata1s in a mouse model led to anemia, rescued by a murine ActRIIB-Fc (RAP-536). Finally, RNA-seq analysis of samples from the Phase 3 MEDALIST trial revealed that responders to Luspatercept had a higher proportion of GATA1s compared to non-responders. Moreover, the increase RBCs post-treatment was linked to a relative decrease in GATA1s isoform. Our study indicates that GDF11-mediated SMAD2 activation results in an increase in functionally impaired GATA1 isoforms, consequently contributing to anemia and influencing responses to Luspatercept in MDS.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View Supplementary table for transcripts that are alternatively spliced in non-responders upon Luspatercept in the MEDALIST trial

View

Version history
  • Version 1 (May 27, 2025): In-Press Preview
Advertisement
Advertisement