Robert Lyle Bowman, Ph.D.

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Assistant Professor of Cancer Biology
Department: Cancer Biology

Contact information
421 Curie Blvd
Philadelphia, PA 19104
BA (Molecular Cellular Biology Honors)
Vanderbilt University, 2010.
PhD (Cancer Biology (Mentor: Johanna Joyce))
Gerstner Sloan Kettering Graduate Program, 2016.
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Description of Research Expertise

Current Research

We are interested in studying the evolution of cancer development from pre-malignancy through transformation. Hematologic malignancies are an ideal disease model to study classical questions in cancer biology, given sample access and extensive description of the normal hematopoietic differentiation cascade. Genetic studies in acute myeloid leukemia (AML) have revealed a hierarchical arrangement of mutations such that certain mutations are postulated to be acquired either early or late in disease progression. This stepwise acquisition of mutations results in a genetically heterogeneous collection of clones contributing to disease development. Through the progression from pre-malignancy to leukemic transformation, we study the following broad questions:

1) What are the necessary steps for a mutant cell to transform to leukemia?
2) After transformation, how do leukemic cells affect normal non-mutated cells?
3) How can we revert or halt transformed cells early in disease development to prevent disease development?

We approach these questions through an intersection of genomic profiling of patient samples and synthetic biology approaches for modeling disease in mice

Bowman Lab

The major focus of the lab is on the receptor tyrosine kinase, FLT3, which is the most commonly mutated gene in AML and typically presents as a subclonal, late event. Mutations can manifest as internal tandem duplications (ITDs) in the juxtamembrane domain leading to constitutive kinase activation. Despite being mutated in only a subset of leukemic cells, FLT3 mutations are associated with poor prognosis. Tyrosine kinase inhibitors (TKIs e.g. gilteritinib) demonstrate substantive clinical efficacy, but invariably lead to relapse. It remains unclear when a given leukemia is dependent upon FLT3 mutations, and how a subclonal oncogene portends such poor prognosis yet has therapeutic utility. In a broader context, understanding the functional roles of clonal and subclonal mutations in AML initiation and maintenance has fundamental mechanistic and therapeutic implications. Current projects in the lab focus on:

1: Oncogenic dependency in leukemic stem cells We will seek to understand how quiescent leukemic stem cells respond to therapy by juxtaposing chemical vs genetic inhibition. In the long term seek to understand how cooperating mutations influence the quantity and characteristics of this stem cell pool.

2: Evaluating cell of origin in FLT3-driven acute myeloid leukemia. We hypothesize that different cooperating mutations influence the cell of origin of FLT3 driven disease. Our lab will approach this question using inducible mouse models and synthetic biology approaches for cell type specific control. In the long term, we seek to progress towards complete in vivo modeling through the development of novel cell type specific recombinase mouse lines.

3 : Investigate interclonal interactions in leukemic progression. We hypothesize that this stepwise acquisition of mutations results in a genetically diverse ecosystem where clones interact either in supporting or suppressing other genetically distinct clones. Our group will investigate inter-clonal interactions and competition through the lens of FLT3 mutant AML, investigating several key questions including: Does the presence of a FLT3-mutant clone affect the fitness of antecedent clones? To investigate clonal heterogeneity and paracrine interactions we will integrate single cell genomic profiling in clinical isolates and mouse models of subclonal FLT3-mutations, mechanistically evaluate candidate paracrine factors ex vivo, and evaluate their role in disease progression in vivo.

Lab Personnel
Lesley Moreno - Administrative Assistant
Nisarg Shah - Research Specialist D
Angela Youn - Research Specialist A
Michael Bowman PhD - Postdoctoral Researcher
Zhangyi (Eva) Li - Master’s Student
Anushka Gandhi - Summer Intern

Selected Publications

Feng Y, Yuan Q, Newsome RC, Robinson T, Bowman RL, Zuniga AN, Hall KN, Bernsten CM, Shabashvili DE, Krajcik KI, Gunaratne C, Zaroogian ZJ, Venugopal K, Casellas Roman HL, Levine RL, Chatila WK, Yaeger R, Riva A, Jobin C, Kopinke D, Avram D, Guryanova OA: Hematopoietic-specific heterozygous loss of Dnmt3a exacerbates colitis-associated colon cancer. Journal of Experimental Medicine 220(11), Nov 6 2023 Notes: e20230011. doi: 10.1084/jem.20230011.

Robinson TM, Bowman RL, Persaud S, Liu Y, Neigenfind R, Gao Q, Zhang J, Sun X, Miles LA, Cai SF, Sciambi A, Llanso A, Famulare C, Goldberg A, Dogan A, Roshal M, Levine RL, Xiao W: Single-cell genotypic and phenotypic analysis of measurable residual disease in acute myeloid leukemia. Science Advances 9(38), Sep 22 2023 Notes: eadg0488.

Dunbar AJ, Kim D, Lu M, Farina M, Bowman RL, Yang JL, Park Y, Karzai A, Xiao W, Zaroogian Z, O'Connor K, Mowla S, Gobbo F, Verachi P, Martelli F, Sarli G, Xia L, Elmansy N, Kleppe M, Chen Z, Xiao Y, McGovern E, Snyder J, Krishnan A, Hill C, Cordner K, Zouak A, Salama ME, Yohai J, Tucker E, Chen J, Zhou J, McConnell T, Migliaccio AR, Koche R, Rampal R, Fan R, Levine RL, Hoffman R: CXCL8/CXCR2 signaling mediates bone marrow fibrosis and is a therapeutic target in myelofibrosis. Blood 141(20): 2508-2519, May 18 2023 Notes: doi: 10.1182/blood.2022015418.

Schwede R, Jahn K, Miles LA, Bowman RL, Kuipers J, Robinson TM, Ediriwickrema A, Gentles AJ, Levine R, Beerenwinkel N, Takahashi K, Majeti R: Characterizing the order of mutation acquisition in acute myeloid leukemia using large-scale single-cell sequencing Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome 2023.

Stahl M, Derkach A, Farnoud N, Bewersdorf JP, Robinson T, Famulare C, Cho C, Devlin S, Menghrajani K, Patel MA, Cai SF, Miles LA, Bowman RL, Geyer MB, Dunbar A, Epstein-Peterson ZD, McGovern E, Schulman J, Glass JL, Taylor J, Viny AD, Stein EM, Getta B, Arcila ME, Gao Q, Barker J, Shaffer BC, Papadopoulos EB, Gyurkocza B, Perales MA, Abdel-Wahab O, Levine RL, Giralt SA, Zhang Y, Xiao W, Pai N, Papaemmanuil E, Tallman MS, Roshal M, Goldberg AD: Molecular predictors of immunophenotypic measurable residual disease clearance in acute myeloid leukemia. American Journal of Hematology 98(1): 79-89, 2023 Notes: DOI: 10.1002/ajh.26757.

Xu JJ, Alija B, Braunstein S, Pantazi J, Sudunagunta VS, Bowman RL, Viny AD: Cohesin Dependency in Npm1c/+ and Flt3-ITD Mutant Hematopoietic Stem and Progenitor Cells. Blood 140 2022.

Andrew Dunbar, Robert L Bowman, Young Park, Franco Izzo, Robert M Myers, Abdul Karzai, Won Jun Kim, Inés Fernández Maestre, Michael R Waarts, Abbas Nazir, Wenbin Xiao, Max Brodsky, Mirko Farina, Louise Cai, Sheng F Cai, Benjamin Wang, Wenbin An, Julie Yang, Shoron Mowla, Shira E Eisman, Tanmay Mishra, Remie Houston, Emily Guzzardi, Anthony R Martinez Benitez, Aaron D Viny, Richard Koche, Dan A Landau, Ross L Levine: Jak2V617F Reversible Activation Shows an Essential Requirement for Jak2V617F in Myeloproliferative Neoplasms (MPNs). Blood 140 2022.

Robinson T, Bowman RL, Persaud S, Liu Y, Gao Q, Zhang JP, Sun X, Sciambi A, Llanso A, Famulare X: Single cell genotypic and phenotypic analysis of measurable residual disease in acute myeloid leukemia. Blood 140 2022.

Bowman RL, Hennessey RC, Weiss TJ, Tallman DA, Crawford ER, Murphy BM, Webb A, Zhang S, La Perle KM, Burd CJ, Levine RL, Shain AH, Burd CE.: UVB mutagenesis differs in Nras- and Braf-mutant mouse models of melanoma. Life Science Alliance 4(9), 2021 Notes: DOI: 10.26508/lsa.202101135.

Maas RR, Soukup K, Klemm F, Kornete M, Bowman RL, Bedel R, Marie DN, Álvarez-Prado ÁF, Labes D, Wilson A, Brouland JP, Daniel RT, Hegi ME, Joyce JA.: An integrated pipeline for comprehensive analysis of immune cells in human brain tumor clinical samples. Nature Protocols 16(10): 4692-4721, 2021 Notes: DOI: 10.1038/s41596-021-00594-2.

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Last updated: 10/23/2023
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