• Open Access

Stem cell and kinase activity-independent pathway in resistance of leukaemia to BCR-ABL kinase inhibitors

Authors


*Correspondence to: Shaoguang LI,
The Jackson Laboratory,
600 Main Street, Bar Harbor, Maine, USA.
Tel.: 207-28 8-6734
Fax: 207-28 8-6978
E-mail: shaoguang.li@jax.org

Abstract

  • • Introduction
  • • Ph+ leukaemia
  • • Leukaemic stem cells
  • • Identification of CML stem cells in mice
  • • BCR-ABL kinase inhibitors do not completely eradicate CML stem cells
  • • B-ALL stem cells and their sensitivity to kinase inhibitors
  • • SRC kinase may impact B-ALL stem cell functions through activation of the downstream signalling molecule β-catenin
  • • Activation of SRC kinases by BCR-ABL is independent of its kinase activity
  • • Role of SRC kinases in the development of B-ALL
  • • Inhibition BCR-ABL kinase activity and SRC kinase leads to long-term survival of B-ALL mice
  • • Role of SRC kinases in progression of CML to lymphoid blast crisis
  • • Comments and conclusions

Abstract

BCR-ABL tyrosine kinase inhibitors, such as imatinib (Gleevec) are highly effective in treating human Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) in chronic phase but not in terminal acute phase; acquired drug resistance caused mainly by the development of BCR-ABL kinase domain mutations prevents cure of the leukaemia. In addition, imatinib is ineffective in treating Ph+ B-cell acute lymphoblastic leukaemia (B-ALL) and CML blast crisis, even in the absence of the kinase domain mutations. This type of drug resistance that is unrelated to BCR-ABL kinase domain mutations is caused by the insensitivity of leukaemic stem cells to kinase inhibitors such as imatinib and dasatinib, and by activation of a newly-identified signalling pathway involving SRC kinases that are independent of BCR-ABL kinase activity for activation. This SRC pathway is essential for leukaemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis. Apart from BCR-ABL and SRC kinases, stem cell pathways must also be targeted for curative therapy of Ph+ leukaemia.

Ancillary