Impairing Acute Myeloid Leukemia Stem Cells by Disrupting Protein Homeostasis

Acute myeloid leukemia (AML) is an aggressive and often deadly blood cancer that is extremely difficult to cure. One of the biggest challenges in treating AML is a rare group of cancer cells known as leukemia stem cells. These cells are like the roots of the disease; they are resistant to most treatments and able to regrow the cancer even after it appears to be gone. As a result, many patients relapse and the long-term survival rate remains dismally low. My research focuses on understanding what makes leukemia stem cells resistant to therapy so that we can develop new strategies to target and eliminate them, and to finally cure AML.

Leukemia stem cells hijack many of their resilience properties from normal blood-forming stem cells. Recently, our lab discovered an entirely new process utilized by normal blood-forming stem cells to tolerate stress and preserve their self-sustaining, regenerative potential. This process is required by stem cells to collect misfolded proteins – the equivalent of cellular trash – by trapping them in protective cages called aggresomes. When stem cells cannot form these “trash cages”, the buildup of toxic proteins causes stem cells to break down and malfunction.

Now, in new studies, I found that leukemia stem cells also form aggresomes. This raises the exciting possibility that leukemia stem cells depend on this pathway for survival. If true, disrupting this protein trash collecting system might be a new way to preferentially kill leukemia stem cells. The goal of my research is to explore and test this possibility.

Aggresomes have never been studied in AML. By exploring aggresomes in leukemia stem cells my research could uncover an entirely new strategy to treat AML that could bring lasting cures to patients.