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Hamza Celik, Ph.D.
The Role of Jarid2 in Leukemic Transformation of Myelodysplastic Syndromes

Hamza Celik, Ph.D.

Washington University

2018 Funding recipient

The Role of Jarid2 in Leukemic Transformation of Myelodysplastic Syndromes

EvansMDS Young Investigator Award

PROJECT SUMMARY

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell (HSC) disorders characterized by inefficient hematopoiesis. Up to 30% of patients progress to secondary acute myeloid leukemia (sAML). Post-MDS sAML patients have a poor prognosis with an average survival of less than six months. To date, no effective therapy exists for post-MDS sAML, and the mechanisms of transformation remain unclear. The clonal evolution of MDS to sAML is driven by acquisition of co-operating genetic mutations. Recent studies have identified deletions of JARID2, a member of the Polycomb Repressive Complex 2 (PRC2) complex in approximately 6.5% of post-MDS/MPN sAML patients (Puda et al., 2012; Am J Hem. 2012). These deletions are mostly heterozygous involving the loss of the short arm of chromosome 6, which contains only the JARID2 gene, delete all of the gene, and occur during the transformation to sAML. JARID2 deletions are not reported in de novo AML, suggesting that JARID2 acts as a tumor suppressor in chronic myeloid neoplasms such as MDS. We have used novel genetic mouse models to study the role of Jarid2 in chronic myeloid disorders. In combination with prototypical MPN (Jak2V617F) or MDS (Idh2R140Q) driver mutations, deletion of Jarid2 in the hematopoietic compartment either accelerated development of MPN (Jak2V617F background) or drove transformation to sAML (Idh2R140Q background) (manuscript in revision at Cancer Cell). In a non-disease background, Jarid2 was determined to recruit PRC2 to gene bodies, epigenetically repressing self-renewal pathways in hematopoietic progenitor cells. Loss of Jarid2 conveyed ectopic self-renewal potential to multipotent progenitor cells (MPPs), a population with only transient repopulating capacity under normal circumstances. We identified a possible mechanism through which loss of Jarid2 contributes to leukemic transformation in the loss of PRC2-mediated repressive histone marks in the proto-oncogenes Runx1t1 and Mycn in MPPs. These studies establish Jarid2 as a bona fide hematopoietic tumor suppressor and delineate how self-renewal programs are epigenetically silenced during hematopoietic differentiation, and that dysregulation of this process can lead to malignant transformation. In this proposal, I aim to leverage novel genetic mouse models and primary MDS patient samples to determine the mechanisms by which JARID2 regulates MDS tumor suppression.

PUBLICATIONS

Hamza Celik, Won Kyun Koh, Ashley C. Kramer, Elizabeth L. Ostrander, Cates Mallaney, Daniel A.C. Fisher, Jingyu Xiang, William C. Wilson,1 Andrew Martens, Alok Kothari, Gregory Fishberger, Eric Tycksen, Darja Karpova, Eric J. Duncavage, Youngsook Lee, Stephen T. Oh, and Grant A. Challen, JARID2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells, Cancer Cell 2018, doi: 10.1016/j.ccell.2018.10.008