Therapeutic efforts for Philadelphia chromosome positive (Ph+) leukemia have focused on targeting mainly BCR-ABL kinase activity with kinase inhibitors, since it has generally been believed that shutting down BCR-ABL kinase activity will completely inhibit its functions, leading to inactivation of downstream signaling pathways. Inhibition of BCR-ABL kinase activity by imatinib mesylate (Gleevec) is highly effective in treating human Ph+ chronic myeloid leukemia (CML) in chronic phase, but not Ph+ B-cell acute lymphoblastic leukemia (B-ALL) and CML blast crisis. The reasons for this are not well understood, but the fact that imatinib is a strong inhibitor of BCR-ABL kinase activity suggests that BCR-ABL kinase activity-independent pathways also play a critical role in the development of both forms of Ph+ leukemia. We have previously shown that the SRC family kinases LYN, HCK, and FGR are activated by BCR-ABL in pre-B leukemic cells and are required for the development of B-ALL (

Hu et al,
Nat Genet
36
:
453
,
2004
). Others have shown that cells from imatinib-resistant patients imatinib expressed an activated form of LYN (
Donato et al,
Blood
101
:
690
,
2003
), and that a BCR-ABL mutant with no kinase activity was still able to activate HCK (
Warmuth et al,
J Biol Chem
272
:
33260
,
1997
). Based on these observations, we hypothesized that inhibition of BCR-ABL kinase by imatinib might not inactivate SRC kinases activated by BCR-ABL in pre-B leukemic cells, which may explain the relatively poor activity of imatinib against Ph+ B-ALL and lymphoid blast crisis CML. We find that SRC kinases activated by BCR-ABL remain fully active in imatinib-treated mouse leukemic cells and this BCR-ABL kinase activity-independent pathway is essential for leukemic cell survival and proliferation. Blockade of this pathway also prevents CML transition to lymphoid blast crisis. In mice with B-ALL, inhibition solely of BCR-ABL kinase activity by imatinib is not curative, but inhibition of both SRC and BCR-ABL kinase activities by the novel, oral, multi-targeted kinase inhibitor dasatinib (BMS-354825), while not killing leukemic stem cells, affords complete remission, maintained as long as treatment is continued. In these mice, we identified the B-ALL leukemic stem cells as B220+CD43+ pro-B cells. CML mice treated with dasatinib lived significantly longer than those treated with imatinib, which correlated with significantly lower numbers of BCR-ABL-expressing leukemic cells in bone marrow, peripheral blood, and spleens of dasatinib-treated CML mice versus placebo- or imatinib-treated mice. However, neither dasatinib nor imatinib were curative in these mice, which was attributed to an inability of both drugs to completely kill Lin-c-kit+CD34-Hoe- CML stem cells. Our studies indicate that complete eradication of leukemic cells in B-ALL and CML mice requires not only targeting BCR-ABL kinase activity-dependent and SRC-dependent pathways, but also killing BCR-ABL-expressing stem cells insensitive to both imatinib and dasatinib. However, the rapid and striking hematologic response of B-ALL mice to dasatinib suggests that the pro-B progenitors with acquired self-renewal capacity are the major source of highly proliferating B-lymphoid leukemic cells in B-ALL mice, and that complete inhibition of growth of this leukemic population with dasatinib could achieve long-term survival in B-ALL.

Topics:
bcr-abl tyrosine kinase, burkitt's lymphoma, leukemia, philadelphia chromosome, phosphotransferases, signal pathway, signal transduction pathways, stem cells, imatinib mesylate, leukemia, b-cell, acute

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2005, The American Society of Hematology
2005
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