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May 18, 2011

Scientists Figure Out Resistance Mechanism of ALL to Tyrosine Kinase Inhibitors

  • Scientists have identified the zinc finger transcription factor BCL6 as a key player in the mechanism by which acute lymphoblastic leukemia (ALL) becomes resistant to tyrosine kinase inhibitors (TKIs). Their studies in a mouse model of drug-resistant leukemia have shown that treating animals using both a TKI inhibitor and a compound that blocks BCL6 boosted the therapeutic effects of treatment and prolonged survival, with no apparent toxicity.

    The research team, led by Markus Müschen, M.D., at University of California, San Francisco (UCSF) and the Children’s Hospital of Los Angeles, reports its findings in Nature in a paper titled “BCL6 enables Ph1 acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition.”

    BCL6 is a known proto-oncogene that is often translocated in diffuse large B-cell lymphoma (DLBCL), where it acts to suppress p-53-mediated apoptosis, Dr. Muschen and colleagues explain. When they looked at gene-expression changes in TKI-treated leukemias, they identified BCL6 as one of the top ranking in a set of recurrent gene-expression changes. TKI-induced upregulation of BCL6 mRNA levels was confirmed in multiple leukemia subtypes carrying oncogenic tyrosine kinases.

    Focusing further on Philadelpha chromosome (Ph)-positive ALL,  the researchers showed that in response to TKI treatment, BCR-ABL1 ALL cells upregulate BCL6 protein levels by approximately 90-fold, to similar levels found in DLBCL. They claim this upregulation represents a novel defence mechanism that leads to transcriptional inactivation of the p53 pathway and enables leukemia cells to survive TKI treatment.

    The team’s studies then confirmed that BCL6-deficient leukemia cells failed to inactivate p53 and were particularly sensitive to TKI treatment, while leukemia cells in which the BCL6 gene had been knocked out remained poised to undergo cellular senescence.

    When they subsequently tested the effects of a selective BCL6 inhibitor called RI-BPI on the self-renewal capacity of primary Ph+ ALL cells and the initiation of leukemia in a mouse xenograft model, they found the drug reduced colony formation and delayed progression of leukemia. Testing the BCL6 inhibitor in ALL cells in which p53 had been knocked out significantly dampened its inhibitory effects, confirming that the activity of BCL6 is at least partly p53-dependent.

    To test the effect of BCL6 inhibition on TKI resistance, Dr. Muschen and colleagues cultured four primary Ph+ ALLs in the presence or absence of the TKI imatinib, RI-BPI, or a combination of both. Initially all four Ph1 ALL cases responded to imatinib treatment but subsequently rebounded and were no longer sensitive to imatinib. Although RI-BPI alone showed only slight effects, combining RI-BPI and imatinib rapidly induced cell death and effectively prevented a rebound in all four cases.

    They next examined the effect of imatinib/RI-BPI combinations on primary TKI-resistance in Ph+ ALL. Four human Ph+ ALL cell lines that lacked BCR-ABL1 kinase mutations but which were highly refractory to imatinib were treated either with or without imatinib, RI-BPI, or a combination of both. Imatinib alone was ineffective therapeutically, whereas combining the drug with RI-BPI potentiated the effect of imatinib on the refractory ALL cells.

    Moving on to in vivo studies, the researchers transplanted fluorescently labeled primary Ph+ ALL cells into mice and treated the recipient animals with nilotinib (which is more effective in mice than imatinib), or a combination of nilotinib and RI-BPI. Subsequent imaging showed that repeated injections of the BCL6 inhibitor enhanced the effects of nilotinib.

    While all mice treated with nilotinib alone succumbed to leukemia within 99 days, 7/8 mice treated with the nilotinib/RI-BPI combination were still alive after 140 days. Additional studies in a model of full-blown mouse leukemia confirmed that combining TKI therapy with RI-BPI effectively prolonged survival.

    Although transcription factors have been considered intractable therapeutic targets, the recent development of a small molecule inhibitor against BCL6 holds promise for effectively targeting TKI resistance in patients with Ph+ ALL,” the authors conclude. “Because TKI resistance develops in virtually all cases of Ph+  ALL, it appears particularly important to target this novel pathway of TKI-resistance.”


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