Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia

Kathryn G. Roberts, Ryan D. Morin, Jinghui Zhang, Martin Hirst, Yongjun Zhao, Xiaoping Su, Shann Ching Chen, Debbie Payne-Turner, Michelle L. Churchman, Richard C. Harvey, Xiang Chen, Corynn Kasap, Chunhua Yan, Jared Becksfort, Richard P. Finney, David T. Teachey, Shannon L. Maude, Kane Tse, Richard Moore, Steven JonesKaren Mungall, Inanc Birol, Michael N. Edmonson, Ying Hu, Kenneth E. Buetow, I. Ming Chen, William L. Carroll, Lei Wei, Jing Ma, Maria Kleppe, Ross L. Levine, Guillermo Garcia-Manero, Eric Larsen, Neil P. Shah, Meenakshi Devidas, Gregory Reaman, Malcolm Smith, Steven W. Paugh, William E. Evans, Stephan A. Grupp, Sima Jeha, Ching Hon Pui, Daniela S. Gerhard, James R. Downing, Cheryl L. Willman, Mignon Loh, Stephen P. Hunger, Marco A. Marra, Charles G. Mullighan

Research output: Contribution to journalArticle

396 Scopus citations

Abstract

Genomic profiling has identified a subtype of high-risk B-progenitor acute lymphoblastic leukemia (B-ALL) with alteration of IKZF1, a gene expression profile similar to BCR-ABL1-positive ALL and poor outcome (Ph-like ALL). The genetic alterations that activate kinase signaling in Ph-like ALL are poorly understood. We performed transcriptome and whole genome sequencing on 15 cases of Ph-like ALL and identified rearrangements involving ABL1, JAK2, PDGFRB, CRLF2, and EPOR, activating mutations of IL7R and FLT3, and deletion of SH2B3, which encodes the JAK2-negative regulator LNK. Importantly, several of these alterations induce transformation that is attenuated with tyrosine kinase inhibitors, suggesting the treatment outcome of these patients may be improved with targeted therapy.

Original languageEnglish (US)
Pages (from-to)153-166
Number of pages14
JournalCancer cell
Volume22
Issue number2
DOIs
StatePublished - Aug 14 2012

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Roberts, K. G., Morin, R. D., Zhang, J., Hirst, M., Zhao, Y., Su, X., Chen, S. C., Payne-Turner, D., Churchman, M. L., Harvey, R. C., Chen, X., Kasap, C., Yan, C., Becksfort, J., Finney, R. P., Teachey, D. T., Maude, S. L., Tse, K., Moore, R., ... Mullighan, C. G. (2012). Genetic Alterations Activating Kinase and Cytokine Receptor Signaling in High-Risk Acute Lymphoblastic Leukemia. Cancer cell, 22(2), 153-166. https://doi.org/10.1016/j.ccr.2012.06.005