Resistance to Imatinib of Bcr/Abl P190 Lymphoblastic Leukemia Cells

Abstract

Around 20% of patients with acute lymphoblastic leukemia are Philadelphia chromosome positive (Ph-positive acute lymphoblastic leukemia) and express the Bcr/Abl tyrosine kinase. Treatment with the tyrosine kinase inhibitor Imatinib is currently standard for chronic myelogenous leukemia, which is also caused by Bcr/Abl. However, Imatinib has shown limited efficacy for treating Ph-positive acute lymphoblastic leukemia. In our study, we have investigated the effect of Imatinib therapy on murine P190 Bcr/Abl lymphoblastic leukemia cells. Three of four cultures were very sensitive to treatment with 5 Amol/L Imatinib. Significant cell death also initially occurred when the same cultures were treated in the presence of stromal support. However, after 6 days, remaining cells started to proliferate vigorously. The Bcr/Abl tyrosine kinase present in the cells that were now able to multiply in the presence of 5 Amol/L Imatinib was still inhibited by the drug. In concordance with this, the Abl ATP-binding pocket domain of Bcr/Abl in the resistant cells did not contain point mutations which would make the protein Imatinib resistant. The effect of stroma in selecting Imatinibresistant lymphoblasts did not require direct cell-cell contact. SDF-1a could substitute for the presence of stromal cells. Our results show that stroma selects Imatinib-resistant Bcr/Abl P190 lymphoblasts that are less dependent on Bcr/Abl tyrosine kinase activity. Therefore, therapy for Ph-positive acute lymphoblastic leukemia, aimed at interfering with the protective effect of stroma in combination with Imatinib, could be of benefit for the eradication of the leukemic cells. (Cancer Res 2006; 66(10): 5387-93)

Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis

“…Recently, Mishra et al provided evidence that CXCL12 produced by stromal cells is responsible for protecting Bcr/Abl lymphoblasts from imatinib-induced cell death. 25 In contrast to our findings, they found that the protective effect is mediated by soluble CXCL12 produced by MSC and independent of direct contact of lymphoma cells with stroma. However, biological differences between lymphoblasts and CML progenitors may account for this discrepancy as protection mediated by cell contact between stroma and other leukemias has been previously reported.…”

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

“…Although encouraging, these observations do not address the possibility that tumor environment may indirectly impact drug efficacy. For example, stromal-mediated protection of leukemia cells in bone marrow from the anticancer activity of tyrosine kinase inhibitors has been reported recently (44,45). Likewise, our data identify Hsp90-dependent, osteoclastmediated protection of certain solid tumors from Hsp90 inhibitors as a potentially important mechanism of chemoresistance that must be overcome to achieve the optimal clinical benefit of these highly promising molecularly targeted drugs.…”

CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells

“…BCR-ABL -expressing lymphoblasts (40). In our system, the prosurvival effects of MSC on imatinib-induced growth inhibition of KBM-5 cells were blocked by AMD3465, suggesting that the CXCR4 up-regulation induced by imatinib and bone marrow stroma promotes survival of CML cells.…”