CBAP modulates Akt-dependent TSC2 phosphorylation to promote Rheb-mTORC1 signaling and growth of T-cell acute lymphoblastic leukemia

Yun-Jung Chiang,Hsin-Fang Yang-Yen,Lee-Yung Shih,Wei-Ting Liao,Yu-Guang Chen,Jeffrey Jong-Young Yen,Shih-Hao Wang,Ching-Liang Ho,Shiu-Feng Huang,Kun-Chin Ho

doi:10.1038/s41388-018-0507-6

Abstract

High-frequency relapse remains a clinical hurdle for complete remission of T-cell acute lymphoblastic leukemia (T-ALL) patients, with heterogeneous dysregulated signaling profiles—including of Raf-MEK-ERK and Akt-mTORC1-S6K signaling pathways—recently being implicated in disease outcomes. Here we report that GM-CSF/IL-3/IL-5 receptor common β-chain-associated protein (CBAP) is highly expressed in human T-ALL cell lines and many primary tumor tissues and is required to bolster leukemia cell proliferation in tissue culture and for in vivo leukemogenesis in a xenograft mouse model. Downregulation of CBAP markedly restrains expansion of leukemia cells and alleviates disease aggravation of leukemic mice. Transcriptomic profiling and molecular biological analyses suggest that CBAP acts upstream of Ras and Rac1, and functions as a modulator of both Raf-MEK–ERK and Akt-mTORC1 signaling pathways to control leukemia cell growth. Specifically, CBAP facilitated Akt-dependent TSC2 phosphorylation in cell-based assays and in vitro analysis, decreased lysosomal localization of TSC2, and elevated Rheb-GTP loading and subsequent activation of mTORC1 signaling. Taken together, our findings reveal a novel oncogenic contribution of CBAP in T-ALL leukemic cells, in addition to its original pro-apoptotic function in cytokine-dependent cell lines and primary hematopoietic cells, by demonstrating its functional role in the regulation of Akt-TSC2-mTORC1 signaling for leukemia cell proliferation. Thus, CBAP represents a novel therapeutic target for many types of cancers and metabolic diseases linked to PI3K-Akt-mTORC1 signaling.

Highlights

IntroductionThe remission rate has significantly improved over the past decade, T-cell acute lymphoblastic leukemia (T-ALL) remains a therapeutic challenge due to the high frequency of induction failure [2] and early relapse, which is mostly resistant to further treatment [3]
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk leukemia subtype that accounts for 10–15% of pediatric and 25% of adult ALL cases [1]
We first observed that CBAP protein expression was higher in a Jurkat T-ALL cell line than in purified human peripheral T lymphocytes (CD3+ T cells) (Fig. 1a), but these latter expressed a higher level of CBAP mRNA than Jurkat T cells (Supplementary Fig. 1a)

Summary

Introduction

The remission rate has significantly improved over the past decade, T-ALL remains a therapeutic challenge due to the high frequency of induction failure [2] and early relapse, which is mostly resistant to further treatment [3]. Molecular abnormalities that have frequently been reported in T-ALL include activation mutations of Notch and JAK1 and inactivation mutations of PTEN and FBXW7 [4]. The PI3K-Akt-mTOR signaling axis is an important contributory pathway for T-cell leukemia [5, 6]. It is frequently upregulated in patients with T-ALL and its activation is correlated with poor prognosis, therapeutic resistance, and disease relapse [5, 7,8,9]. Deletion of mTOR complex-1 (mTORC1) in a T-ALL mouse model resulted in profound cell-cycle arrest and efficient eradication of T-ALL cells [10, 11], suggesting that mTORC1 can integrate signals from the PI3K-Akt and MEK–ERK signaling pathways to CBAP modulates Akt-dependent TSC2 phosphorylation to promote Rheb-mTORC1 signaling and growth of T-cell

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Results

Conclusion