Emerging Implications of LKB1 Liver Kinase B1 Gene as Tumor Suppressor Gene

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Ola A. Hussein, Hany A. Labib, Rasha Haggag, Maha Mahmoud Hamed Sakr


Background: The LKB1 tumor suppressor is a serine/threonine kinase that functions as master regulator of cell growth, metabolism, survival and polarity. LKB1 is frequently mutated in human cancers and research spanning the last two decades have begun decoding the cellular pathways deregulated following LKB1 inactivation, Liver kinase B1 (LKB1) is a major activator of the AMP-dependent kinase/mammalian target of rapamycin pathway. The prevalence and the specificity of LKB1 gene mutation in acute myeloid leukemia (AML) have not been well established.

Summary: Work from preclinical studies in cell lines, xeno-grafts and GEMMs predict that metabolic therapies, targeted therapeutics targeting LKB1 vulnerabilities will be most effective in combination. Several recent studies show that loss of Lkb1 in adult mice leads to loss of hematopoietic stem cell (HSC) quiescence, resulting in depletion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. LKB1-deficient HSCs and bone marrow cell exhibit reduced mitochondrial membrane potential and depletion of cellular ATP. These data define an essential role of the LKB1 in restricting HSC entry into the cell cycle and in maintaining energy homeostasis through AMPK-dependent and AMP K­independent mechanisms. Moreover, several studies showed that the anti-diabetic drug metaformin (an LKB1/AMPK activator) exerted significant anti-leukemia cell activity in AML and T-cell acute lymphoblastic leukemia cells through inhibiting mTOR activity. These studies demonstrated that the LKB1/AMPK tumor-suppressor axis is generally functional in hematopoietic cancer and that pharmacological intervention activating this pathway may represent a new target in anticancer therapy.

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