Experiments in zebrafish have revealed a mechanism that may drive relapse in human T-cell acute lymphoblastic leukemia (T-ALL).
Researchers identified a subset of T-ALL cells that spontaneously acquired activation of the Akt pathway.
This increased the frequency of leukemia-propagating cells (LPCs) and mediated resistance to treatment with dexamethasone. However, adding an Akt inhibitor to treatment overcame this resistance.
“The Akt pathway appears to be a major driver of treatment resistance,” said study author David Langenau, PhD, of the Harvard Stem Cell Institute in Boston.
“We also show that this same pathway increases overall growth of leukemic cells and increases the fraction of cells capable of driving relapse.”
Dr Langenau and his colleagues described these findings in Cancer Cell.
Previous research had shown that, if LPCs are retained following treatment, they will initiate disease relapse. And LPC frequency can increase over time. However, it was not clear if this was the result of continued clonal evolution or if a clone with high LPC frequency out-competed other cells.
So Dr Langenau and his colleagues used zebrafish models to study T-ALL clones. The team observed functional variation within individual clones and identified clones that enhanced growth rate and leukemia-propagating potential with time.
A subset of these clones acquired Akt pathway activation, which increased the number of LPCs by activating mTORC1. The cells also exhibited an elevated growth rate, which may have resulted from stabilizing the Myc protein.
Furthermore, the LPCs proved resistant to treatment with dexamethasone. But the researchers were able to reverse this resistance by combining dexamethasone with the Akt inhibitor MK2206. This approach proved effective both in zebrafish models and in human T-ALL cells.
“Our work will likely help in identifying patients that are prone to relapse and would benefit from co-treatment with inhibitors of the Akt pathway and typical front-line cancer therapy,” said Jessica Blackburn, PhD, a member of Dr Langenau’s lab.
She and her colleagues are now hoping to identify other mutations that lead to relapse, thereby pinpointing potential drug targets for patients with aggressive leukemia.
