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

N Engl J Med. Volume 49, Issue 8: p.3080-3087, 11 September 2014, 10.1056/NEJMoa1403088

Background: 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.).

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Supplemental Data Files

• GDC Manifests
  • Controlled-Access Data Download Manifest (6 Files)
  • Open-Access Data Download Manifest (22 Files)
  • WGS CGI Files Download Manifest (305 Files)
• Copy Number
  • TARGET ALL P2 Copy Number Array Level 1 Data (Controlled)
  • TARGET ALL P2 Copy Number Array Level 2 Data (Controlled)
  • TARGET ALL P2 Copy Number Array Level 3 Data
  • TARGET ALL P2 Copy Number Array Metadata
• Gene Expression Array
  • TARGET ALL P2 Gene Expression Array Level 1 Data
  • TARGET ALL P2 Gene Expression Array Level 2 Data
  • TARGET ALL P2 Gene Expression Array Level 3 Data
  • TARGET ALL P2 Gene Expression Array Metadata
• Methylation Array
  • TARGET ALL P2 Methylation Array Level 1 Data
  • TARGET ALL P2 Methylation Array Level 1 Data (Controlled)
  • TARGET ALL P2 Methylation Array Level 2 Data
  • TARGET ALL P2 Methylation Array Level 3 Data
  • TARGET ALL P2 Methylation Array Design Information
  • TARGET ALL P2 Methylation Array Metadata
• mRNA-Seq
  • TARGET ALL P2 mRNA-Seq Level 3 Data
  • TARGET ALL P2 mRNA-Seq Level 3 Data (Controlled)
  • TARGET ALL P2 mRNA-Seq Metadata
• miRNA-Seq
  • TARGET ALL P2 miRNA-Seq Level 3 Data
  • TARGET ALL P2 miRNA-Seq Metadata
• WGS
  • TARGET ALL P1 and P2 WGS L3 Data
  • TARGET ALL P1 and P2 WGS L3 Data (Controlled)
  • TARGET ALL P1 and P2 WGS L4 Data
  • TARGET ALL P2 and P2 WGS Metadata
• WXS
  • TARGET ALL P2 WXS Level 3 Data
  • TARGET ALL P2 WXS Level 3 Data (Controlled)
  • TARGET ALL P2 WXS Design Information
  • TARGET ALL P2 WXS Metadata
• Miscellaneous Files
  • TARGET ALL P2 Sample Matrix

Additional Resources

• TARGET-ALL-P2 at SRA (link is external) NCBI

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