RUNX1 deficiency cooperates with SRSF2 mutation to induce multilineage hematopoietic defects characteristic of MDS

Author:

Huang Yi-Jou12,Chen Jia-Yu3ORCID,Yan Ming1,Davis Amanda G.12ORCID,Miyauchi Sayuri1,Chen Liang3ORCID,Hao Yajing3,Katz Sigrid1,Bejar Rafael1ORCID,Abdel-Wahab Omar4,Fu Xiang-Dong13ORCID,Zhang Dong-Er125

Affiliation:

1. 1Moores Cancer Center, UC San Diego (UCSD), La Jolla, CA

2. 2Department of Molecular Biology, UCSD, La Jolla, CA

3. 3Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA

4. 4Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY

5. 5Department of Pathology, UC San Diego, La Jolla, CA

Abstract

Abstract Myelodysplastic syndromes (MDSs) are a heterogeneous group of hematologic malignancies with a propensity to progress to acute myeloid leukemia. Causal mutations in multiple classes of genes have been identified in patients with MDS with some patients harboring more than 1 mutation. Interestingly, double mutations tend to occur in different classes rather than the same class of genes, as exemplified by frequent cooccurring mutations in the transcription factor RUNX1 and the splicing factor SRSF2. This prototypic double mutant provides an opportunity to understand how their divergent functions in transcription and posttranscriptional regulation may be altered to jointly promote MDS. Here, we report a mouse model in which Runx1 knockout was combined with the Srsf2 P95H mutation to cause multilineage hematopoietic defects. Besides their additive and synergistic effects, we also unexpectedly noted a degree of antagonizing activity of single mutations in specific hematopoietic progenitors. To uncover the mechanism, we further developed a cellular model using human K562 cells and performed parallel gene expression and splicing analyses in both human and murine contexts. Strikingly, although RUNX1 deficiency was responsible for altered transcription in both single and double mutants, it also induced dramatic changes in global splicing, as seen with mutant SRSF2, and only their combination induced missplicing of genes selectively enriched in the DNA damage response and cell cycle checkpoint pathways. Collectively, these data reveal the convergent impact of a prototypic MDS-associated double mutant on RNA processing and suggest that aberrant DNA damage repair and cell cycle regulation critically contribute to MDS development.

Publisher

American Society of Hematology

Subject

Hematology

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