This week, we profile a recent publication in Leukemia from Kerri Thomas (pictured, right) in the lab of
David Rawlings (left) at Seattle Children’s / UW.
1. Can you provide a brief overview of your lab’s current research focus?
One key focus within our lab is to better understand signaling events that alter lymphocyte development, activation, and function in the context of immunodeficiency, autoimmunity, and malignancies. We utilize unique (human and murine) in vitro B lineage culture models, gene editing, and knock-in/knock-out models to evaluate the developmental and functional consequences of altered expression of key proteins including: signaling receptors (i.e. IL7R, BAFF/TACI receptor), tyrosine kinases or phosphatases (BTK, PTPN22), adapter proteins (SH2B3), and lipid enzymes (PI3 kinase).
2. What is the significance of the findings in this publication?
Activating mutations in the interleukin-7 receptor (IL-7R) have been identified in T- and B-cell acute lymphoblastic leukemias (ALLs), but their precise role in leukemogenesis is unclear. In this study, we developed a murine knock-in model to evaluate the effects of a leukemia-specific activating IL-7R mutation (aIL7R) on early B lymphopoiesis and leukemogenesis. Heterozygous, B cell-restricted expression of aIL7R was sufficient to lead to spontaneous B-ALL, providing the first definitive example that aIL7R is capable of initiating leukemia. Further, loss-of-function mutations in the signaling adaptor SH2B3 or the lymphoid transcription factor IKZF1, events that frequently co-occur with IL7R in human ALL, cooperate with aIL7R to increase leukemia incidence.
Through detailed characterization of these models we found that aIL7R murine leukemias recapitulate multiple genomic and proteomic features of human Ph-like ALL including clonal expansion; acquisition of somatic mutations in clinically-relevant genes like Kras; and activation of JAK/STAT, mTOR, and a unique “BCR-like” signaling programs. Importantly, we also utilized the adoptive transfer of primary leukemic cells to assess responsiveness to small molecules targeting these pathways in immune-competent hosts. We believe that this new genetically engineered mouse model (GEMM), which closely mimics human Ph-like ALL, will serve as a robust new platform for additional biochemical studies and for in vivo testing of candidate therapeutics.
3. What are the next steps for this research?
We are continuing work to identify therapeutics that are effective at controlling aIL7R murine leukemia growth in vivo. Using our preclinical serial transplantation system, we will test combinations of kinase inhibitors that target the JAK/STAT, mTOR, and “BCR-like” signaling arms. We will also investigate the upstream events mediating the “BCR-like” signaling program in both murine and human IL-7R mutant ALL. Finally, we are interested in using this model to similarly evaluate the role of aIL7R in early T cell development and T-ALL.
4. This work was funded by:
This work was supported by the National Institutes of Health (TL1-TR000422, DP3-DK111802, NCI-R01CA201135-A1, 1K08CA184418, 1U01CA232486, 1U01CA243072, 1K08DK114568-01), Department of Defense Translational Team Science Award (CA180683P1), the V Foundation for Cancer Research, the Seattle Children’s Research Institute Center for Immunity and Immunotherapies (CIIT) Program for Cell and Gene Therapy (PCGT), the Children’s Guild Association Endowed Chair in Pediatric Immunology, and the Hansen Investigator in Pediatric Innovation Endowment.
