About

Michael G. Kharas, PhD, is a cancer biologist who studies RNA regulators of self-renewal in both normal and leukemic hematopoiesis. His research focuses on identifying critical pathways in hematopoietic cells, including those involved in leukemia. Dr. Kharas's work includes investigating how RNA binding proteins and molecular pathways influence leukemia cell proliferation, differentiation, and resistance to therapy. His contributions have advanced understanding of the molecular mechanisms underlying leukemia and have identified potential targets for therapeutic intervention.

Research topics

• Biochemistry
• Biology
• Chemistry
• Cell biology
• Cancer research
• Computational biology

Selected publications

• Abstract 7101: Discovery of first-in-class YTHDC1 small molecule inhibitors for the treatment of MYC-driven cancers

  Cancer Research · 2026-04-03

  article

  Abstract The m6A reader protein YTHDC1 is essential for cancer cell survival, through its ability to form nuclear biomolecular condensates that stabilize oncogenic transcripts such as MYC. Here, we report a new class of potent, selective, orally bioavailable small-molecule inhibitors of YTHDC1. These compounds occupy the RNA binding pocket of YTHDC1 and disrupt its interaction with m6A-modified RNA at nanomolar potency in both biochemical and cellular assays. They display high selectivity for YTHDC1 over other YTH family members, selectively dissolve m6A-dependent YTHDC1 condensates without affecting unrelated condensate systems, and exhibit clean profiles across broad kinase and safety panels. The optimized leads are drug-like, orally bioavailable and possess favorable ADME and in vivo properties. Pharmacological inhibition of YTHDC1 disrupts oncogenic YTHDC1 condensates and robustly suppresses MYC signaling resulting in growth arrest, differentiation, and apoptosis of acute myeloid leukemia (AML) and additional cancer cell types, while sparing normal hematopoietic cells. These optimized inhibitors display strong single-agent anti-tumor activity across heme and solid tumor models including AML, small cell lung cancer and neuroendocrine prostate cancer. Moreover, YTHDC1 inhibition shows pronounced synergy with standard of care agents such as venetoclax in AML. Collectively, these findings establish YTHDC1 as a tractable therapeutic target for MYC-driven malignancies. Citation Format: Richard C. Centore, Mark Charles, Mansi Arora, Marius Rebmann, Michael J. Rawling, Jerome Cattin, Xuejing Yang, Emily Batchelor, Matthew Watson, Nagakumar Bharatham, Alexander Howarth, Seema Qamar, Laura Andraghetti, Andrew Seeber, Michael G. Kharas, Sam Cohen, Martin Kulander, Tuomas Knowles, Shilpi Arora. Discovery of first-in-class YTHDC1 small molecule inhibitors for the treatment of MYC-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7101.

  PublisherDOI

• Abstract 3983: Condensate dynamics drive adaptive METTL3 inhibitor resistance

  Cancer Research · 2026-04-03

  articleSenior author

  Abstract The RNA methyltransferase METTL3, catalyzing N6-methyladenosine (m6A) modification, is implicated in oncogenesis. METTL3 inhibitors have shown potent anti-tumor efficacy across diverse preclinical models and are being tested in early-phase clinical trials. However, how cells fundamentally and dynamically respond to disruption of the m6A RNA methylation machinery and what drives resistance to the catalytic inhibition of METTL3 remains unknown. Using genome-wide CRISPR sensitization and resistance screens in sensitive and resistant cancer models, we identify the nuclear m6A-reader YTHDC1 as a critical determinant of METTL3 inhibition response. Genetic depletion of YTHDC1 markedly sensitizes cells to METTL3 inhibitor (METTL3i) treatment in vitro and in vivo across solid and hematologic cancers, and its overexpression drives primary resistance. A YTHDC1-condensate imaging screen identified YTHDC1 interactor PABPN1, a PAXT complex component and a resistance hit from our CRISPR screen, as a negative regulator of YTHDC1 condensate dynamics. PABPN1 overexpression restores METTL3i sensitivity in resistant models, whereas its loss induces resistance, highlighting that the state of YTHDC1 nuclear condensates functionally mediate METTL3i response. Mechanistically, catalytic blockade of METTL3 remodels YTHDC1 condensates, increasing their intensity, size, and number while reducing their biophysical dynamics in sensitive cancer models and patient samples. In contrast, healthy human blood cells retain dynamic condensates, and resistant cancers display static condensates. Integrating direct RNA nanopore m6A mapping, bulk-RNAseq and quantitative proteomics in YTHDC1-overexpression model, we find that residual m6A modification persist on transcripts, and YTHDC1 drives restoration of MYC/BCL-2 programs upon METTL3 inhibition. Furthermore, YTHDC1 enhances binding to MYC and BCL-2 mRNAs under METTL3i treatment, preserving their translation despite global m6A loss. Accordingly, MYC overexpression phenocopies YTHDC1-mediated resistance to METTL3i, confirming its functional relevance. Therapeutically, co-targeting with a newly developed YTHDC1 inhibitor or the clinically approved BCL-2 inhibitor venetoclax synergistically enhances METTL3i efficacy in vitro and in vivo in clinically relevant models including AML patient-derived xenografts. Together, these findings uncover adaptive reorganization of the m6A machinery across hematologic and solid cancers. The YTHDC1 pathway and its condensate state act as predictive biomarkers and enhancers of therapeutic efficacy in METTL3-targeted cancers. Combinatorial targeting of METTL3 and YTHDC1/BCL-2 as a strategy to overcome therapeutic resistance. Citation Format: Xuejing Yang, Maria Eleftheriou, Eliza Yankova, Siân Evans, Theodore M. Nelson, Isaac Wakiro, Emily Batchelor, Kathryn Chang, Joao M. Dias, Aspen Pierson, Genevieve Girard, Rhoshini Raghuraman, Demetrios Aspris, Vidur Tandon, Grace Han, Lydia P. Tsamouri, Hanzhi Luo, James Russell, Maria T. Bejar, Maria P. Alcolea, Ajay Edakkara, Muxin Gu, Rupert Öllinger, Malgorzata Gozdecka, Brian J. Huntly, Roland Rad, Lina Vasiliauskaitė, Yaara Ofir-Rosenfeld, George S. Vassiliou, Yuanming Cheng, Mansi Arora, Richard C. Centore, Christopher E. Mason, Oliver Rausch, Shilpi Arora, Konstantinos Tzelepis, Michael G. Kharas. Condensate dynamics drive adaptive METTL3 inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3983.

  PublisherDOI

• Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation

  Science · 2026-01-01 · 4 citations

  articleOpen accessCorresponding

  Somatic mutations that increase the fitness of hematopoietic stem cells (HSCs) drive their expansion in clonal hematopoiesis (CH) and predispose individuals to blood cancers. Population variation in the growth rate and potential of mutant clones suggests that genetic factors may confer resilience against CH. Here, we identified a noncoding regulatory variant, rs17834140-T, that protects against CH and myeloid malignancies by selectively down-regulating the RNA-binding protein MSI2 in HSCs. By modeling variant effects and mapping MSI2 binding targets, we uncovered an RNA network that maintains human HSCs and influences CH risk. Variant rs17834140-T was associated with slower CH expansion, and stem cell MSI2 levels modified ASXL1 -mutant HSC clonal dominance. These findings leverage natural resilience to illuminate posttranscriptional regulation in human HSCs, suggesting that inhibition of MSI2 or its targets could be rational strategies for blood cancer prevention.

  PublisherOA PDFDOI

• Crip2 preserves hematopoietic stem and progenitor cell production through inhibition of Notch signals

  Development · 2026-01-28

  articleOpen access

  Hematopoietic stem and progenitor cells (HSPCs) have multilineage potential and sustain long-term self-renewal. Deriving patient-specific HSPCs has immense therapeutic potential to overcome the shortage of compatible donors for transplantation. In zebrafish, hemogenic endothelium (HE) is a specialized collection of dorsal aortic endothelial cells (ECs) that give rise to HSPCs. Our data reveal that Cysteine rich intestinal protein 2 (Crip2) has a previously unrecognized function in establishing the proper EC environment for HSPC specification. To investigate the requirement of Crip2, we generated loss-of-function alleles in crip2 and crip3, a gene family member with cardiovascular expression. crip2-/-;crip3-/- (cripDM) embryos exhibit decreased HSPC emergence with impaired lineage derivative production. Single cell RNA-sequencing of kdrl:mCherry+ ECs reveals upregulation of vascular development signature and failure to repress Notch signals during the vital transition of HE specification to HSPC emergence. Moreover, our data underscore that inhibition of Notch promotes HSPC generation in cripDM embryos and Crip genes operate through NF-κB to limit Notch. Identification of Crip2 as a novel regulator of Notch repression in HE will enhance our understanding of cues necessary to improve human HSPC production in vitro.

  PublisherDOI

• pTα enhances mRNA translation and potentiates CAR T cells for solid tumor eradication

  Cell · 2025-12-02 · 2 citations

  article
  PublisherDOI

• Supplementary Tables 1-6 from Patient-Derived iPSCs Faithfully Represent the Genetic Diversity and Cellular Architecture of Human Acute Myeloid Leukemia

  2025-11-24

  articleOpen access

  <p>Table S1. Patient characteristics. AML: acute myeloid leukemia; MDS: myelodysplastic syndrome; MPN: myeloproliferative neoplasm; ET: essential thrombocythemia; PBMCs: peripheral blood mononuclear cells; BMMCs: bone marrow mononuclear cells; PDX: patient-derived xenografts Table S2. All patient samples used in this study with genetic characterization and reprogramming outcomes. Blue font denotes partially reprogrammed (as opposed to bona fide iPSC) colonies and clones. Table S3. All AML-iPSC lines phenotypically characterized. Table S4. Top 50 upregulated genes (highest log2 fold change) in each cluster. Table S5. Primers used for genotyping. Table S6. Primers used for qRT-PCR analyses.</p>

  PublisherOA PDFDOI

• N6-Methyladenosine: an RNA modification as a central regulator of cancer

  Nature reviews. Cancer · 2025-12-08 · 6 citations

  articleOpen access
  PublisherOA PDFDOI

• Author Correction: ChromaFold predicts the 3D contact map from single-cell chromatin accessibility

  Nature Communications · 2025-01-15

  erratumOpen access
  PublisherOA PDFDOI

• Kitlo hematopoietic stem cells exhibit distinct lymphoid-primed chromatin landscapes that enhance thymic reconstitution

  Nature Communications · 2025-07-04 · 5 citations

  articleOpen access

  Abstract Hematopoietic stem cells (HSC) with multilineage potential are critical for T cell reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). The Kit lo HSC subset is enriched for multipotential precursors, but their T cell potential remains poorly characterized. Using a preclinical allo-HCT mouse model, we demonstrate that Kit lo HSCs provide superior thymic recovery and T cell reconstitution, resulting in improved immune responses to post-transplant infection. Kit lo HSCs with augmented bone marrow (BM) lymphopoiesis mitigate age-associated thymic alterations and enhance T cell recovery in middle-aged mice. Mechanistically, chromatin profiling reveals Kit lo HSCs exhibiting higher activity of lymphoid-specifying transcription factors, such as, ZBTB1. Zbtb1 deletion diminishes HSC engraftment and T cell potential; by contrast, reinstating Zbtb1 in megakaryocytic-biased Kit hi HSCs rescues hematopoietic engraftment and T cell potential in vitro and in vivo. Furthermore, age-associated decline in Kit lo HSCs is associated with diminished T lymphopoietic potential in aged BM precursors; meanwhile, Kit lo HSCs in aged mice maintain enhanced lymphoid potential, but their per-cell capacity is diminished. Lastly, we observe an analogous human BM KIT lo HSC subset with enhanced lymphoid potential. Our results thus uncover an age-related epigenetic regulation of lymphoid-competent Kit lo HSCs for T cell reconstitution.

  PublisherOA PDFDOI

• Inherited resilience to clonal hematopoiesis by modifying stem cell RNA regulation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-26 · 2 citations

  preprintOpen access

  Somatic mutations that increase hematopoietic stem cell (HSC) fitness drive their expansion in clonal hematopoiesis (CH) and predispose to blood cancers. Although CH frequently occurs with aging, it rarely progresses to overt malignancy. Population variation in the growth rate and potential of mutant clones suggests the presence of genetic factors protecting against CH, but these remain largely undefined. Here, we identify a non-coding regulatory variant, rs17834140-T, that significantly protects against CH and myeloid malignancies by downregulating HSC-selective expression and function of the RNA-binding protein MSI2. By modeling variant effects and mapping MSI2 binding targets, we uncover an RNA network that maintains human HSCs and influences CH risk. Importantly, rs17834140-T is associated with slower CH expansion rates in humans, and stem cell MSI2 levels modify ASXL1-mutant HSC clonal dominance in experimental models. These findings leverage natural resilience to highlight a key role for post-transcriptional regulation in human HSCs, and offer genetic evidence supporting inhibition of MSI2 or its downstream targets as rational strategies for blood cancer prevention.

  PublisherOA PDFDOI

Recent grants

• NIH Grant K01DK084261

  NIH · $784k · 2014

• Identification of therapeutic targets for leukemia stem cells in AML-iPSC models

  NIH · $2.6M · 2018–2023

• Identification of therapeutic targets for leukemia stem cells in AML-iPSC models

  NIH · $625k · 2018–2023

• Uncovering the role for MSI2 network in hematopoietic stem cells

  NIH · $5.8M · 2014–2032

• Mechanisms of epitranscriptomic regulation in cancer

  NIH · $5.9M · 2014–2029

Frequent coauthors

• D. Gary Gilliland

  39 shared

• Benjamin L. Ebert

  39 shared

• Fátima Al‐Shahrour

  Spanish National Cancer Research Centre

  36 shared

• Rachel Okabe

  36 shared

• George Q. Daley

  Harvard University

  35 shared

• David A. Scheinberg

  Kettering University

  35 shared

• Christina Leslie

  34 shared

• Christopher J. Lengner

  California University of Pennsylvania

  34 shared

Labs

• Michael Kharas LabPI

Education

• PhD, Molecular Biology and Biochemistry

  University of California Irvine

  2006

Awards & honors

• Leukemia and Lymphoma Society Career Development Award (2017…
• Alex Lemonade Stand Foundation ‘A’ Award (2016)
• American Society of Hematology Junior Faculty Scholar Award…
• Kimmel Scholar Award (2013)
• V-Scholar Award (2013)