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Supplementary Figure S10 from Comprehensive Ex Vivo Transposon Mutagenesis Identifies Genes That Promote Growth Factor Independence and Leukemogenesis

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posted on 2023-03-30, 23:48 authored by Yabin Guo, Barrett L. Updegraff, Sunho Park, Deniz Durakoglugil, Victoria H. Cruz, Sarah Maddux, Tae Hyun Hwang, Kathryn A. O'Donnell

Phosphorylation of STAT5 in Ba/F3 cells overexpressing CIS genes.

Funding

The Cancer Prevention Research Institute of Texas

The American Cancer Society

The Welch Foundation

The Sidney Kimmel Foundation

CPRIT Scholar in Cancer Research and a Kimmel Scholar

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ARTICLE ABSTRACT

Aberrant signaling through cytokine receptors and their downstream signaling pathways is a major oncogenic mechanism underlying hematopoietic malignancies. To better understand how these pathways become pathologically activated and to potentially identify new drivers of hematopoietic cancers, we developed a high-throughput functional screening approach using ex vivo mutagenesis with the Sleeping Beauty transposon. We analyzed over 1,100 transposon-mutagenized pools of Ba/F3 cells, an IL3-dependent pro-B-cell line, which acquired cytokine independence and tumor-forming ability. Recurrent transposon insertions could be mapped to genes in the JAK/STAT and MAPK pathways, confirming the ability of this strategy to identify known oncogenic components of cytokine signaling pathways. In addition, recurrent insertions were identified in a large set of genes that have been found to be mutated in leukemia or associated with survival, but were not previously linked to the JAK/STAT or MAPK pathways nor shown to functionally contribute to leukemogenesis. Forced expression of these novel genes resulted in IL3-independent growth in vitro and tumorigenesis in vivo, validating this mutagenesis-based approach for identifying new genes that promote cytokine signaling and leukemogenesis. Therefore, our findings provide a broadly applicable approach for classifying functionally relevant genes in diverse malignancies and offer new insights into the impact of cytokine signaling on leukemia development. Cancer Res; 76(4); 773–86. ©2015 AACR.

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