AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications.

The mammalian target of rapamycin (mTOR) serine/threonine
kinase is the catalytic subunit of two multi-protein complexes,
referred to as mTORC1 and mTORC2. Signaling downstream
of mTORC1 has a critical role in leukemic cell biology by
controlling mRNA translation of genes involved in both cell
survival and proliferation. mTORC1 activity can be downmodulated
by upregulating the liver kinase B1/AMP-activated
protein kinase (LKB1/AMPK) pathway. Here, we have explored
the therapeutic potential of the anti-diabetic drug, metformin
(an LKB1/AMPK activator), against both T-cell acute lymphoblastic
leukemia (T-ALL) cell lines and primary samples
from T-ALL patients displaying mTORC1 activation. Metformin
affected T-ALL cell viability by inducing autophagy and
apoptosis. However, it was much less toxic against proliferating
CD4þ T-lymphocytes from healthy donors. Western blot
analysis demonstrated dephosphorylation of mTORC1 downstream
targets. Unlike rapamycin, we found a marked inhibition
of mRNA translation in T-ALL cells treated with metformin.
Remarkably, metformin targeted the side population of T-ALL
cell lines as well as a putative leukemia-initiating cell subpopulation
(CD34þ/CD7/CD4) in patient samples. In conclusion,
metformin displayed a remarkable anti-leukemic activity,
which emphasizes future development of LKB1/AMPK activators
as clinical candidates for therapy in T-ALL.
Leukemia (2012) 26, 91–100; doi:10.1038/leu.2011.269;
published online 4 October 2011