Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia.

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.

• Authors: 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 Jones, Karen 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
• Journal: Cancer cell (Cancer Cell) Vol. 22 Issue 2 Pg. 153-66 (Aug 14 2012) ISSN: 1878-3686 [Electronic] United States
• PMID: 22897847 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• EBF1 protein, human
• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• RNA, Messenger
• Receptors, Cytokine
• Trans-Activators
• Protein-Tyrosine Kinases
• Receptor, Platelet-Derived Growth Factor beta

Topics

• Animals
• Base Sequence
• Cell Transformation, Neoplastic
• DNA Mutational Analysis
• Enzyme Activation (drug effects)
• Gene Expression Regulation, Leukemic (drug effects)
• Gene Rearrangement (genetics)
• Genetic Predisposition to Disease
• Humans
• Mice
• Molecular Sequence Data
• Mutation (genetics)
• Oncogene Proteins, Fusion (genetics)
• Philadelphia Chromosome
• Phosphorylation (drug effects)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (enzymology, genetics)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (genetics)
• RNA, Messenger (genetics, metabolism)
• Receptor, Platelet-Derived Growth Factor beta (genetics)
• Receptors, Cytokine (genetics)
• Recurrence
• Risk Factors
• Sequence Deletion (genetics)
• Signal Transduction (drug effects, genetics)
• Trans-Activators (genetics)