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

Li S, Li D - J. Cell. Mol. Med. (2007 Nov-Dec)

Bottom Line: 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.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.Apart from BCR-ABL and SRC kinases, stem cell pathways must also be targeted for curative therapy of Ph+ leukaemia.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, ME, USA. shaoguang.li@jax.org

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.

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Simultaneous targeting of both leukaemic stem cells and highly proliferative leukaemic cells may lead to cure of Ph+ leukaemia. Treatment with BCR-ABL kinase inhibitors does not cure CML and B-ALL induced by BCR-ABL in mice, this is likely due to the inability of these inhibitors to kill leukaemic stem cells. Therefore, combination of anti-stem cell agents and BCR-ABL kinase inhibitors would be a promising therapeutic strategy for Ph+ leukaemia.
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fig02: Simultaneous targeting of both leukaemic stem cells and highly proliferative leukaemic cells may lead to cure of Ph+ leukaemia. Treatment with BCR-ABL kinase inhibitors does not cure CML and B-ALL induced by BCR-ABL in mice, this is likely due to the inability of these inhibitors to kill leukaemic stem cells. Therefore, combination of anti-stem cell agents and BCR-ABL kinase inhibitors would be a promising therapeutic strategy for Ph+ leukaemia.

Mentions: Most challenging issue in therapy of Ph+ leukaemia deals with leukaemic stem cells. Although dasatinib could help achieve long-term control of BALL in mice, curative drug therapy of this disease would require targeting quiescent leukaemic stem cells [62] in addition to BCR-ABL kinase activity and SRC-dependent pathways. Identification of CML and B-ALL stem cells in mice [19] is significant, as it provides a model system for studying the biology of leukaemic stem cells. Identification of pro-B leukaemic cells as stem cells for B-ALL is important, as it indicates that pro-B progenitors could acquire self-renewal capacity to become the major source of highly proliferating B-lymphoid leukaemic cells in BALL mice. Therefore, complete inhibition of growth of this leukaemic population could achieve long-term survival of B-ALL mice. This also promotes the effort in testing whether other progenitor lineages could also acquire stem-like properties. It will be important to assess whether the stem cells identified in leukaemic mice can be similarly found in Ph+ leukaemia patients. Finally, insensitivity of leukaemic stem cells in mice to inhibition by both imatinib and dasatinib [19] prompts us to identify unknown pathways in leukaemic stem cells for developing curative therapies for Ph+ leukaemia (Fig. 2). It is important to mention that in human CML patients the ineffectiveness of kinase inhibitors to completely eradicate leukaemic cells could also be due to the pre-existing BCR-ABL kinase domain mutations, as shown by the elegant work from Ottmann's group [63]. It will be critical to investigate whether these mutations exist in leukaemic stem cells of CML patients before they are treated with kinase inhibitors. On the other hand, there are other kinase inhibitors that inhibit multiple kinases in cancer cells. For example, the Aurora kinase VX-680 (MK-0457) suppresses tumour cell growth and also inhibits BCR-ABL kinase including imatinib-resistant mutant BCRABL [64–69]. It is worth testing whether this kind of inhibitors would have an inhibitory effect on leukaemic stem cells.


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

Li S, Li D - J. Cell. Mol. Med. (2007 Nov-Dec)

Simultaneous targeting of both leukaemic stem cells and highly proliferative leukaemic cells may lead to cure of Ph+ leukaemia. Treatment with BCR-ABL kinase inhibitors does not cure CML and B-ALL induced by BCR-ABL in mice, this is likely due to the inability of these inhibitors to kill leukaemic stem cells. Therefore, combination of anti-stem cell agents and BCR-ABL kinase inhibitors would be a promising therapeutic strategy for Ph+ leukaemia.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401291&req=5

fig02: Simultaneous targeting of both leukaemic stem cells and highly proliferative leukaemic cells may lead to cure of Ph+ leukaemia. Treatment with BCR-ABL kinase inhibitors does not cure CML and B-ALL induced by BCR-ABL in mice, this is likely due to the inability of these inhibitors to kill leukaemic stem cells. Therefore, combination of anti-stem cell agents and BCR-ABL kinase inhibitors would be a promising therapeutic strategy for Ph+ leukaemia.
Mentions: Most challenging issue in therapy of Ph+ leukaemia deals with leukaemic stem cells. Although dasatinib could help achieve long-term control of BALL in mice, curative drug therapy of this disease would require targeting quiescent leukaemic stem cells [62] in addition to BCR-ABL kinase activity and SRC-dependent pathways. Identification of CML and B-ALL stem cells in mice [19] is significant, as it provides a model system for studying the biology of leukaemic stem cells. Identification of pro-B leukaemic cells as stem cells for B-ALL is important, as it indicates that pro-B progenitors could acquire self-renewal capacity to become the major source of highly proliferating B-lymphoid leukaemic cells in BALL mice. Therefore, complete inhibition of growth of this leukaemic population could achieve long-term survival of B-ALL mice. This also promotes the effort in testing whether other progenitor lineages could also acquire stem-like properties. It will be important to assess whether the stem cells identified in leukaemic mice can be similarly found in Ph+ leukaemia patients. Finally, insensitivity of leukaemic stem cells in mice to inhibition by both imatinib and dasatinib [19] prompts us to identify unknown pathways in leukaemic stem cells for developing curative therapies for Ph+ leukaemia (Fig. 2). It is important to mention that in human CML patients the ineffectiveness of kinase inhibitors to completely eradicate leukaemic cells could also be due to the pre-existing BCR-ABL kinase domain mutations, as shown by the elegant work from Ottmann's group [63]. It will be critical to investigate whether these mutations exist in leukaemic stem cells of CML patients before they are treated with kinase inhibitors. On the other hand, there are other kinase inhibitors that inhibit multiple kinases in cancer cells. For example, the Aurora kinase VX-680 (MK-0457) suppresses tumour cell growth and also inhibits BCR-ABL kinase including imatinib-resistant mutant BCRABL [64–69]. It is worth testing whether this kind of inhibitors would have an inhibitory effect on leukaemic stem cells.

Bottom Line: 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.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.Apart from BCR-ABL and SRC kinases, stem cell pathways must also be targeted for curative therapy of Ph+ leukaemia.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, ME, USA. shaoguang.li@jax.org

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.

Show MeSH
Related in: MedlinePlus