Biomedical Graduate Studies

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 Ljmoreno@upenn.edu
Nisarg Shah - Research Specialist D
Angela Youn - Research Specialist A
Michael Bowman PhD - Postdoctoral Researcher
Roopsha Bandopadhyay - PhD Student - Bioengineering
Anushka Gandhi - Undergraduate Researcher
Shreeya Gounder - Undergraduate Researcher