Blocking Mcl-1 Cures Mouse Model of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) cells have been found to depend on the antiapoptotic protein Mcl-1 for survival, and it is expected that drugs that inhibit Mcl-1 could be used to successfully treat the disease.

AML frequently relapses after the initial rounds of chemotherapy. Drug resistance in AML has been attributed to high levels of the antiapoptotic Bcl-2 family members Bcl-xL and Mcl-1 (induced myeloid leukemia cell differentiation protein).

In the current study, investigators at The Walter and Eliza Hall Institute (Melbourne, Australia) used a mouse AML model to compare the effects of blocking Mcl-1 activity to that of blocking the activity of other Bcl-2 family members.

They reported in the January 15, 2012, issue of the journal Genes & Development that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-xL, Bcl-2, or Bcl-w, caused the death of AML cells and could cure the disease in AML-afflicted mice.

First author Dr. Stefan Glaser, a postdoctoral researcher at The Walter and Eliza Hall Institute, said, “Other research has already shown that high levels of Mcl-1 are associated with resistance to chemotherapy. What we have shown is that without Mcl-1, AML cells rapidly die. This is exciting because it identifies Mcl-1 as a potential target for new anticancer medications.”

“We found that many types of AML cells were very dependent on Mcl-1 to survive”, said Dr. Glaser. “When Mcl-1 was depleted from the AML cells, they rapidly died. Importantly, noncancerous blood cells were much less susceptible to dying when Mcl-1 was depleted. This means that, if Mcl-1 inhibitors are developed, there may be a “treatment window” in which AML cells are killed, while normal blood cells that are essential for health can be spared, helping patients recover from the treatment much better. We are optimistic that in the future, Mcl-1 inhibitors may improve the outlook for AML patients, who currently have a very poor prognosis.”

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