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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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Therapeutically Targetable ALK Mutations in Leukemia.

Julia E Maxson1, Monika A Davare2, Samuel B Luty1

  • 1Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon.

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|June 3, 2015
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Summary
This summary is machine-generated.

Genome sequencing identified novel ALK kinase mutations in aggressive leukemias. These ALK mutations responded to targeted ALK inhibitors, suggesting a new personalized treatment approach for certain leukemia patients.

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Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Genome sequencing is uncovering a wide spectrum of mutations in leukemia.
  • Targeted therapies based on specific genetic mutations offer new treatment avenues.

Purpose of the Study:

  • To identify and characterize novel mutations in the anaplastic lymphoma kinase (ALK) gene in leukemia patients.
  • To evaluate the therapeutic potential of ALK inhibitors against leukemia with ALK mutations.

Main Methods:

  • Whole genome sequencing was performed on leukemia patient samples.
  • Functional assays were used to assess the transforming activity of identified ALK mutations.
  • Sensitivity to ALK kinase inhibitors, including crizotinib, was tested.

Main Results:

  • Two patients with acute myeloid leukemia and B-cell acute lymphoblastic leukemia were found to have point mutations in the ALK gene.
  • These ALK mutations were located in the extracellular domain and demonstrated potent transforming activity.
  • The identified ALK mutations conferred sensitivity to ALK kinase inhibitors, such as crizotinib.

Conclusions:

  • ALK kinase domain mutations represent a potential therapeutic target in specific aggressive leukemias.
  • Targeted inhibition of ALK may offer a personalized treatment strategy for leukemia patients with these mutations.