SON inhibits megakaryocytic differentiation via repressing RUNX1 and the megakaryocytic gene expression program in acute megakaryoblastic leukemia

Abstract

A high incidence of acute megakaryoblastic leukemia (AMKL) in Down syndrome patients implies that chromosome 21 genes have a pivotal role in AMKL development, but the functional contribution of individual genes remains elusive. Here, we report that SON, a chromosome 21-encoded DNA- and RNA-binding protein, inhibits megakaryocytic differentiation by suppressing RUNX1 and the megakaryocytic gene expression program. As megakaryocytic progenitors differentiate, SON expression is drastically reduced, with mature megakaryocytes having the lowest levels. In contrast, AMKL cells express an aberrantly high level of SON, and knockdown of SON induced the onset of megakaryocytic differentiation in AMKL cell lines. Genome-wide transcriptome analyses revealed that SON knockdown turns on the expression of pro-megakaryocytic genes while reducing erythroid gene expression. Mechanistically, SON represses RUNX1 expression by directly binding to the proximal promoter and two enhancer regions, the known +23 kb enhancer and the novel +139 kb enhancer, at the RUNX1 locus to suppress H3K4 methylation. In addition, SON represses the expression of the AP-1 complex subunits JUN, JUNB, and FOSB which are required for late megakaryocytic gene expression. Our findings define SON as a negative regulator of RUNX1 and megakaryocytic differentiation, implicating SON overexpression in impaired differentiation during AMKL development.

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Fig. 1: SON is minimally expressed in differentiated megakaryocytes but is aberrantly upregulated in AMKL.
Fig. 2: SON expression is decreased during PMA-induced megakaryocytic differentiation and SON knockdown leads to the onset of megakaryocytic differentiation in AMKL cells.
Fig. 3: SON knockdown in AMKL cells reveals the genome-wide transcriptome changes and the affected cellular pathways.
Fig. 4: SON knockdown leads to upregulation of pro-megakaryocytic genes.
Fig. 5: SON depletion leads to upregulation of RUNX1, resulting in activation of RUNX1-regulated megakaryocytic transcription programs.
Fig. 6: SON directly binds to the RUNX1 promoter and two enhancer regions and represses RUNX1 transcription.
Fig. 7: SON represses transcription of JUN, JUNB, and FOSB through direct promoter binding.
Fig. 8: Models of the SON function in regulating megakaryocytic differentiation and its proposed contribution to AMKL development.

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Acknowledgements

We thank Dr. Shai Izraeli (Tel Aviv University) for kindly providing the CMY and CMK cell lines. This work was supported by the NIH grants (R01CA190688 and R01CA236911 to E.E.A. and R01HL136432 to S.T.L.) and institutional support from the University of Alabama at Birmingham School of Medicine, Department of Pathology, and the UAB O’Neal Comprehensive Cancer Center (to E.E.A.).

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Correspondence to Eun-Young Erin Ahn.

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Vukadin, L., Kim, JH., Park, E.Y. et al. SON inhibits megakaryocytic differentiation via repressing RUNX1 and the megakaryocytic gene expression program in acute megakaryoblastic leukemia. Cancer Gene Ther (2020). https://doi.org/10.1038/s41417-020-00262-9

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