HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.

AbstractBACKGROUND:
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.
METHODS:
We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL.
RESULTS:
Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib.
CONCLUSIONS:
Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).
AuthorsKathryn G Roberts, Yongjin Li, Debbie Payne-Turner, Richard C Harvey, Yung-Li Yang, Deqing Pei, Kelly McCastlain, Li Ding, Charles Lu, Guangchun Song, Jing Ma, Jared Becksfort, Michael Rusch, Shann-Ching Chen, John Easton, Jinjun Cheng, Kristy Boggs, Natalia Santiago-Morales, Ilaria Iacobucci, Robert S Fulton, Ji Wen, Marcus Valentine, Cheng Cheng, Steven W Paugh, Meenakshi Devidas, I-Ming Chen, Shalini Reshmi, Amy Smith, Erin Hedlund, Pankaj Gupta, Panduka Nagahawatte, Gang Wu, Xiang Chen, Donald Yergeau, Bhavin Vadodaria, Heather Mulder, Naomi J Winick, Eric C Larsen, William L Carroll, Nyla A Heerema, Andrew J Carroll, Guy Grayson, Sarah K Tasian, Andrew S Moore, Frank Keller, Melissa Frei-Jones, James A Whitlock, Elizabeth A Raetz, Deborah L White, Timothy P Hughes, Jaime M Guidry Auvil, Malcolm A Smith, Guido Marcucci, Clara D Bloomfield, Krzysztof Mrózek, Jessica Kohlschmidt, Wendy Stock, Steven M Kornblau, Marina Konopleva, Elisabeth Paietta, Ching-Hon Pui, Sima Jeha, Mary V Relling, William E Evans, Daniela S Gerhard, Julie M Gastier-Foster, Elaine Mardis, Richard K Wilson, Mignon L Loh, James R Downing, Stephen P Hunger, Cheryl L Willman, Jinghui Zhang, Charles G Mullighan
JournalThe New England journal of medicine (N Engl J Med) Vol. 371 Issue 11 Pg. 1005-15 (Sep 11 2014) ISSN: 1533-4406 [Electronic] United States
PMID25207766 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • CRLF2 protein, human
  • DNA, Neoplasm
  • Protein Kinase Inhibitors
  • Receptors, Cytokine
  • Protein-Tyrosine Kinases
Topics
  • Adolescent
  • Adult
  • Animals
  • Child
  • Child, Preschool
  • DNA, Neoplasm (analysis)
  • Female
  • Genome, Human
  • Heterografts
  • Humans
  • Infant
  • Male
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • Philadelphia Chromosome
  • Polymorphism, Single Nucleotide
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, metabolism, mortality)
  • Protein Kinase Inhibitors (therapeutic use)
  • Protein-Tyrosine Kinases (antagonists & inhibitors)
  • Receptors, Cytokine (genetics, metabolism)
  • Signal Transduction (genetics)
  • Survival Analysis
  • Young Adult

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: