Aberrant GSK3β nuclear localization promotes AML growth and drug resistance

Abstract

Acute myeloid leukemia (AML) is a devastating disease with poor patient survival. As targetable mutations in AML are rare, novel oncogenic mechanisms are needed to define new therapeutic targets. We identified AML cells that exhibit an aberrant pool of nuclear glycogen synthase kinase 3β (GSK3β). This nuclear fraction drives AML growth and drug resistance. Nuclear, but not cytoplasmic, GSK3β enhances AML colony formation and AML growth in mouse models. Nuclear GSK3β drives AML partially by promoting nuclear localization of the NF-κB subunit, p65. Finally, nuclear GSK3β localization has clinical significance as it strongly correlates to worse patient survival (n = 86; hazard ratio = 2.2; P < .01) and mediates drug resistance in cell and animal models. Nuclear localization of GSK3β may define a novel oncogenic mechanism in AML and represent a new therapeutic target.

Glycogen synthase kinase-3 beta inhibitors as novel cancer treatments and modulators of antitumor immune responses

“…79 Recent data suggested that GSK-3β localization has clinical significance with worse patient survival and mediates drug resistance in both in vitro and in vivo. 80 GSK-3β is also upregulated in natural killer (NK) cells from AML patients compared to normal donors. 81 Same study showed that GSK-3β overexpression in NK cells impairs their ability to kill AML cells, while genetic or pharmacological GSK-3β inhibition enhances NK cell cytotoxic activity in human AML mouse models.…”

Crosstalks of GSK3 signaling with the mTOR network and effects on targeted therapy of cancer

“…For the purposes of this review, it is important to point out that a fraction of GSK3 localizes to the nucleus of both healthy and cancer cells [21][22][23][24]. Consistently, some GSK3 substrates (e.g.…”

“…However, there is also evidence showing that a high expression of GSK3β in the nucleus portends a poorer prognosis in renal cell carcinoma (RCC) [105,106] and in AML patients [23].…”

SIRT1 and AROS suppress doxorubicin-induced apoptosis via inhibition of GSK3β activity in neuroblastoma cells

“…GSK3β is mainly known as a cytoplasmic protein, but is also found in the nucleus and mitochondria (Bijur and Jope 2003). Recent studies have shown that nuclear localization of GSK3β is regulated by mTOR complex 1 (mTORC1) (Bautista et al 2018), and nuclear GSK3β facilitates acute myeloid leukemia (AML) cell growth and drug resistance (Ignatz-Hoover et al 2018). However, the regulation of nuclear GSK3β is not well defined.…”