Research
The Kharas lab aims to uncover novel RNA regulators in stem cell biology and development in hopes of improving our understanding of cancer pathogenesis and treatment.
We know that hematopoietic stem cells (HSCs) must negotiate a delicate balance between symmetric division and asymmetric division in order to maintain self-renewal of the HSC compartment and continued development of terminally differentiated hematopoietic effector cells. However, the programs that modulate the switch from symmetric division to asymmetric division are not well understood. Lending particular urgency to the study of this cell-fate switch is recent work suggesting that these same cellular programs are critical to the fundamental process of stem cell disorders. Mechanistic insights into the regulation of cell-fate decisions may inform approaches to bone marrow failure syndromes, differentiation therapy of hematopoietic malignancies, and stem cell expansion for therapeutic benefits. By profiling gene expression in HSCs, we identified an RNA-binding protein called Musashi-2 that is required for normal hematopoietic stem cells and is overexpressed in patients with a worse clinical outcome in acute myeloid leukemia. The musashi gene was first identified in Drosophila in the sensory organ precursor cells regulating the cell-fate decision and modulating asymmetric cell division. Our projects have focused on understanding the MUSASHI RNA binding protein network in both normal and malignant hematopoietic biology.
Disruption of genetic and epigenetic mechanisms and altered signaling networks can promote cancer initiation and progression. While somatic alterations in these pathways leading to tumorigenesis are commonly studied, it remains to be established how processes that affect post-transcriptional and translational regulation of mRNA/protein expression impact cancer development. The wide discrepancy between transcriptional expression and the proteome highlights the importance of this regulation. RBPs are involved in post-transcriptional and co-translational regulation of RNA metabolism. There are over 1,500 distinct RBPs and tens of thousands of different coding and non-coding RNAs that are present in every cell. However, only a small number of these RBPs have been evaluated for their functional relevance. Altogether the RNA-protein and protein-protein interactions comprise the regulatory network of post-transcriptional regulation and mediate cell fate decisions in normal HSCs. Thus, we aim to define the oncogenic riboproteome and reveal the functionally relevant components to aid the discovery of novel therapeutic targets.
We have developed a platform to identify novel factors and RNA regulators that alter self-renewal, cell-fate decisions, and differentiation of HSCs and leukemia. We have established screening strategies to identify small molecules that block and inhibit RNA binding proteins.
Current Projects:
- Characterizing the role of MUSASHI family in normal and leukemic hematopoietic stem cells
- Identifying RNA regulators that have the potential to expand normal hematopoietic stem cells and convert embryonic stem cells to blood
- Developing screening approaches for self-renewal in both normal hematopoietic stem cells and leukemia stem cells in the context of myelodysplastic syndromes and acute myeloid leukemia
- Developing small molecules against RNA binding proteins
- Studying how RNA methylation controls cell fate
- Studying cellular pathways that are altered in induced pluripotent derived AML patient samples
- Understanding altered metabolic programs in normal and malignant stem cells.
Bio
Dr. Michael G. Kharas is an Investigator that leads a laboratory in the Molecular Pharmacology Program at the Memorial Sloan-Kettering Cancer Center (New York, NY, USA) and Professor at Weill Cornell Pharmacology Graduate Program. Dr. Kharas finished his postdoctoral training at Brigham and Women’s Hospital and studied how signaling pathways alters stem cell regulation. In 2011 he started his laboratory at MSK and focused on the controllers of cellular fate in the blood. His laboratory has uncovered new RNA regulators and how they modulate self-renewal, cell-fate decisions, and differentiation in both normal blood development and in myeloid leukemia. Also, his laboratory is developing inhibitors that block the function of RNA regulators as a new therapeutic strategy in cancer. Dr. Kharas has received recognition including the Leukemia Lymphoma Society Scholar Award and American Society of Hematology Scholar Award.
Distincstions:
- Alex Lemonade Stand Foundation A Award
- Leukemia and Lymphoma Society, Career Development Scholar Award
- Top 50 Graduate Alumni “Celebration of Graduate Success Day” University of California Irvine
- DePaul Magazine’s 14 Outstanding Alumni under 40
- Kimmel Scholar Award
- V Scholar Award
- American Society of Hematology Junior Faculty Scholar Award
- Louis V. Gerstner Young Investigator Award
Selected Publications:
Park SM, Miyamoto DK, Han GYQ, Chan M, Curnutt NM, Tran NL, Velleca A, Kim JH, Schurer A, Chang K, Xu W, Kharas MG, Woo CM. Dual IKZF2 and CK1α degrader targets acute myeloid leukemia cells. Cancer Cell. 2023 Apr 10;41(4):726-739.e11. doi: 10.1016/j.ccell.2023.02.010. Epub 2023 Mar 9. PMID: 36898380.
Erazo T, Evans CM, Zakheim D, Chu KL, Refermat AY, Asgari Z, Yang Z, Ferreira MD, Mehta S, Russo MV, Knezevic A, Zhang XP, Chen Z, Fennell M, Garippa R, Seshan V, de Stanchina E, Barbash O, Batlevi CL, Melnick AM, Younes A*, Kharas MG*. TP53 mutations and RNA binding protein MUSASHI2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma. Nat Comm 2022 September 27. 13(5626).
Cheng Y*, Xie W*, Pickering BF, Chu KL, Savino AM, Yang X, Luo H, Nguyen DTT, Mo S, Barin E, Velleca A, Rohwetter T, Patel DJ, Jaffrey SR, Kharas MG*. N6 methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation Cancer Cell. July 2021.
Prieto C, Nguyen DTT, Liu Z,Wheat J, Perez A, Gourkanti S, Chou T, Barin E, Velleca A, Rohwetter T, Barin E, Chow A, Taggart J, Hoskova K, Dhodapkar M, Schurer A, Barlowe TS, Vu LP, Leslie C, Steidl U, Rabadan R, Kharas MG*. Transcriptional control of CBX5 by the RNA binding proteins RBMX/L1 maintain chromatin state in myeloid leukemia. Nat Cancer. July 2021 5: 741-757.