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.

中文翻译：

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CBAP调节依赖Akt的TSC2磷酸化，以促进Rheb-mTORC1信号传导和T细胞急性淋巴细胞白血病的生长。

高频复发仍然是T细胞急性淋巴细胞白血病（T-ALL）患者完全缓解的临床障碍，其信号分布异常不同，包括Raf-MEK-ERK和Akt-mTORC1-S6K信号通路-最近被牵连在疾病结果中。在这里，我们报道GM-CSF / IL-3 / IL-5受体共同的β链相关蛋白（CBAP）在人T-ALL细胞系和许多原发性肿瘤组织中高表达，并且是促进白血病细胞增殖所必需的组织培养和异种移植小鼠模型中的体内白血病发生。CBAP的下调显着抑制白血病细胞的扩张并减轻白血病小鼠的疾病加重。转录组分析和分子生物学分析表明，CBAP作用于Ras和Rac1的上游，并充当Raf-MEK-ERK和Akt-mTORC1信号通路的调节剂，以控制白血病细胞的生长。具体而言，CBAP在基于细胞的测定和体外分析中促进了Akt依赖的TSC2磷酸化，降低了TSC2的溶酶体定位，并增加了Rheb-GTP的负载并随后激活了mTORC1信号传导。综上所述，我们的发现揭示了CBAP在细胞因子依赖性细胞系和原代造血细胞中的原始促凋亡功能，以及其在Akt-调节中的作用，从而揭示了CBAP在T-ALL白血病细胞中的新型致癌作用。 TSC2-mTORC1信号传导白血病细胞增殖。因此，CBAP代表了与PI3K-Akt-mTORC1信号传导相关的许多类型的癌症和代谢性疾病的新型治疗靶标。