Grant Challen, Ph.D.

Assistant Professor
Internal Medicine
Oncology

Cancer Biology Program
Developmental, Regenerative and Stem Cell Biology Program
Molecular Cell Biology Program
Molecular Genetics and Genomics Program

  • 314-362-0987

  • 314-362-0986

  • 314-747-2797

  • Southwest Tower 744

  • grantchallen@wustl.edu

  • www.challenlab.com

  • @challenlab

  • Hematopoietic stem cells, Leukemia stem cells, Epigenetic modifications

  • Understanding the genetic and epigenetic mechanisms that regulate normal and leukemic stem cells

Research Abstract:

Hematopoietic stem cells (HSCs) reside in the bone marrow and are defined by their capacity for lifetime maintenance of the blood and bone marrow, achieved through their differentiation into the myriad cellular components, as well as their ability to generate additional stem cells via self-renewal. The mechanisms that instruct the fate of stem cells toward differentiation versus self-renewal are still relatively poorly understood. A number of transcription factors have been identified as critical for HSC maintenance and self-renewal; however, we have little insight into how these factors are orchestrated by epigenetic mechanisms to ensure blood homeostasis. The central theme of my research is understanding how epigenetic marks such as histone methylation and acetylation, DNA methylation, and 5-hydroxymethylation coordinately act to regulate normal HSC function and how these processes go awry in hematopoietic diseases such as leukemia and lymphoma. We also use various mouse genetic models to study the roles of genetic mutations of different components of the epigenetic machinery in cancers of the blood and bone marrow.

Ongoing projects in the lab include

* The role of DNA methylation in hematopoietic stem cell fate decision
* The functions of epigenetic mutations in leukemias and lymphomas
* Modifying the epigenome for somatic cell reprogramming

Mentorship and Commitment to Diversity Statement:
As mentor, I will not simply lead by example, but instead I will be involved in my mentee’s development. I will do this by being mindful of the mentee’s future by fostering skill sets that are valuable not only to their present work but also to their future careers. As a mentor, I seek to make a contribution to the development of the whole person. Each mentee is different and different goals require different skills, but I will aspire to help you develop certain universal skills—recognizing opportunities, asking questions, acknowledging shortcomings, and communicating effectively.

I am committed to continuing to pursue efforts to enhance diversity, equity and inclusion in our lab and on campus in general. My commitment to promoting diversity and inclusion in science and academia is grounded in personal experience, years of leadership and teaching, and my commitment to training the next generation of scientists. I believe that science / medical education has an essential role in cultivating a biomedical workforce to meet the needs of our diverse communities.


Selected Publications:

Hormaechea-Agulla D, Matatall KA, Le DT, Kain B, Long X, Kus P, Jaksik R, Challen GA, Kimmel M, King KY. "Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling." Cell Stem Cell. 2021 Mar 16:S1934-5909(21)00108-9. PMID: 33743191

Marinaccio C, Suraneni P, Celik H, Volk A, Wen QJ, Ling T, Bulic M, Lasho T, Koche RP, Famulare CA, Farnoud N, Stein B, Schieber M, Gurbuxani S, Root DE, Younger ST, Hoffman R, Gangat N, Ntziachristos P, Chandel NS, Levine RL, Rampal RK, Challen GA, Tefferi A, and Crispino JD. “LKB1/STK11 is a tumor suppressor in the progression of myeloproliferative neoplasms.” Cancer Discov. 2021 doi: 10.1158/2159-8290.CD-20-1353. Online ahead of print.

Ostrander EL, Kramer AC, Mallaney C, Celik H, Koh WK, Fairchild J, Haussler E, Zhang CRC and Challen GA. “Divergent Effects of Dnmt3a and Tet2 Mutations on Hematopoietic Progenitor Cell Fitness.” Stem Cell Reports 2020, 14(4): 551-560.

Zhang CRC, Nix D, Gregory M, Ciorba MA, Ostrander EL, Newberry RD, Spencer DH and Challen GA. “Inflammatory cytokines promote clonal hematopoiesis with specific mutations in ulcerative colitis patients.” Exp Hematol. 2019, 80: 36-41.

Mallaney C, Ostrander EL, Celik H, Kramer AC, Martens A, Kothari A, Koh WK, Haussler E, Iwamori N, Gontarz P, Zhang B and Challen GA. “Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis.” Leukemia 2019, 33(10):2506-2521.

Celik H, Koh WC, Kramer AC, Ostrander EL, Mallaney C, Fisher DAC, Xiang J, Wilson WC, Martens A, Kothari A, Fishberger G, Tycksen E, Karpova D, Duncavage EJ, Lee Y, Oh ST and Challen GA. “Jarid2 Functions as a Tumor Suppressor in Myeloid Neoplasms by Repressing Self-Renewal in Hematopoietic Progenitor Cells.” Cancer Cell 2018, 34(5):741-756.

Jeong M, Park HJ, Celik H, Ostrander EL, Reyes JM, Guzman A, Rodriguez B, Lei Y, Lee Y, Ding L, Guryanova OA, Li W, Goodell MA and Challen GA. "Loss of Dnmt3a Immortalizes Hematopoietic Stem Cells In Vivo." Cell Rep 2018, 23(1):1-10. PMCID: PMC5908249.

Xu Y, Milazzo JP, Somerville TDD, Tarumoto Y, Huang YH, Ostrander EL, Wilkinson JE, Xu Y, Milazzo JP, Somerville TDD, Tarumoto Y, Huang YH, Ostrander EL, Wilkinson JE, Challen GA and Vakoc CR. "A TFIID-SAGA Perturbation that Targets MYB and Suppresses Acute Myeloid Leukemia." Cancer Cell 2018, 33(1):13-28. PMCID: PMC5764110.

Ostrander EL, Mallaney C, Kramer AC, Wilson WC, Zhang B and Challen GA. "The GNASR201C Mutation Associated with Clonal Hematopoiesis Maintains Mouse Long-Term Hematopoietic Stem Cell Potential." Experimental Hematology 2018, 57: 14-20. PMCID: PMC5716908.

Kramer AC, Kothari A, Wilson WC, Celik H, Nikitas J, Mallaney C, Ostrander EL, Eultgen E, Martens A, Valentine MC, Young AL, Druley TE, Figueroa ME, Zhang B and Challen GA. "Dnmt3a regulates T-cell development and suppresses T-ALL transformation." Leukemia 2017, 31(11):2479-2490. PMCID: PMC5636646.

Young AL, Challen GA, Birmann BM and Druley TE. "Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults." Nat Commun 2016, 7:12484. PMCID: PMC4996934.

Yang L, Rodriguez B, Mayle A, Park HJ, Lin X, Luo M, Jeong M, Curry CV, Kim SB, Ruau D, Zhang X, Zhou T, Zhou M, Rebel VI, Challen GA, Göttgens B, Lee JS, Rau R, Li W and Goodell MA. "DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias." Cancer Cell 2016, 29(6):922-934. PMCID: 27505680.

McDonald JI, Celik H, Rois LE, Fishberger G, Fowler T, Rees R, Kramer A, Martens A, Edwards JR and Challen GA. "Reprogrammable CRISPR/Cas9-based system for inducing site-specific DNA methylation." Biol Open 2016, 5(6):866-874. PMCID: PMC4920199.

Celik H, Mallaney C, Kothari A, Eultgen E, Martens A, Miller CA, Hundal J, Klco JM and Challen GA. "Enforced Differentiation of Dnmt3a-null Bone Marrow Leads to Failure with c-Kit Mutations Driving Leukemic Transformation." Blood 2015, 125(4):629-638. PMCID: PMC4304107.

Challen GA*, Sun D, Mayle A, Jeong M, Luo M, Rodriguez B, Mallaney C, Celik H, Yang L, Xia Z, Cullen S, Berg J, Zheng Y, Darlington GJ, Li W and Goodell MA. "Dnmt3a and Dnmt3b have Overlapping and Distinct Functions in Hematopoietic Stem Cells." Cell Stem Cell 2014, 15(3):350-364. PMCID: PMC4163922.

Challen GA, Sun D, Jeong M, Luo M, Jelinek J, Berg JS, Bock C, Vasanthakumar A, Gu H, Xi Y, Liang S, Lu Y, Darlington GJ, Meissner A, Issa JP, Godley LA, Li W, and Goodell MA. "Dnmt3a is Essential for Hematopoietic Stem Cell Differentiation." Nature Genetics 2011, 44(1): 23-31. PMCID: PMC3637952.

Last Updated: 3/27/2021 11:39:49 AM

Model for Dnmt3a action in HSCs. “HSC genes” are mostly unmethylated and expressed in normal HSCs (left). Upon receiving a signal to differentiate, Dnmt3a methylates and silences these regions to permit lineage commitment. This is associated with a loss of H3K4me3. These genes are then repressed in B-cells. Dnmt3a-KO HSCs (right) cannot silence these “HSC genes” so upon receiving a stimulus to differentiate, these genes remain expressed due to lack of methylation and elevated H3K4me3. Upon cell division, the HSC self-renewal pathway remains the default state for Dnmt3a-KO HSCs resulting in their accumulation in the bone marrow. Of the few Dnmt3a-KO HSCs that do differentiate, their progeny show incomplete methylation and repression of “HSC genes.” Nat Genet 2011 Dec 4;44(1):23-31
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