KIT signaling governs differential sensitivity of mature and primitive CML progenitors to tyrosine kinase inhibitors

Amie S. Corbin, Thomas O'Hare, Zhimin Gu, Ira L. Kraft, Anna M. Eiring, Jamshid S. Khorashad, Anthony D. Pomicter, Tian Y. Zhang, Christopher A. Eide, Paul W. Manley, Jorge E. Cortes, Brian J. Druker, Michael W. Deininger

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Imatinib and other BCR-ABL1 inhibitors are effective therapies for chronic myelogenous leukemia (CML), but these inhibitors target additional kinases including KIT, raising the question of whether off-target effects contribute to clinical efficacy. On the basis of its involvement inCMLpathogenesis, we hypothesized that KIT may govern responses of CML cells to imatinib. To test this, we assessed the growth of primary CML progenitor cells under conditions of sole BCR-ABL1, sole KIT, and dual BCR-ABL1/KIT inhibition. Sole BCR-ABL1 inhibition suppressed mature CML progenitor cells, but these effects were largely abolished by stem cell factor (SCF) and maximal suppression required dual BCR-ABL1/KIT inhibition. In contrast, KIT inhibition did not add to the effects of BCR-ABL1 inhibition in primitive progenitors, represented by CD3438 cells. Long-term cultureinitiating cell assays on murine stroma revealed profound depletion of primitive CML cells by sole BCR-ABL1 inhibition despite the presence of SCF, suggesting that primitive CML cells are unable to use SCF as a survival factor upon BCR-ABL1 inhibition. In CD3438 cells, SCF strongly induced pAKTS473 in a phosphoinositide 3- kinase (PI3K)-dependent manner, which was further enhanced by inhibition of BCR-ABL1 and associated with increased colony survival. In contrast, pAKTS473 levels remained low in CD3438 cells cultured under the same conditions. Consistent with reduced response to SCF, KIT surface expression was significantly lower on CD34 38 compared with CD3438 CML cells, suggesting a possible mechanism for the differential effects of SCF on mature and primitive CML progenitor cells.

Original languageEnglish (US)
Pages (from-to)5775-5786
Number of pages12
JournalCancer Research
Volume73
Issue number18
DOIs
StatePublished - Sep 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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