Subcellular Proteome Analysis Reveals Apoptotic Vulnerability of T-Cell Acute Lymphoblastic Leukemia

Abstract

Targeting death receptor-mediated apoptosis in T-cell acute lymphoblastic leukemia (T-ALL), an aggressive disease with poor prognosis, is hindered by the inherent resistance of primary leukemia cells. Knowledge on therapeutic vulnerabilities in these malignant cells will provide opportunities for developing novel combinatory treatments for patients. Using label-free quantitative mass spectrometry and subcellular fractionation techniques, we systematically compared organelle-specific proteomes between Jurkat cells, an in vitro model for T-ALL, and a Jurkat mutant with increased resistance to death receptor-mediated apoptosis. By identifying several differentially regulated protein clusters, our data argued that extensive metabolic reprograming in the mitochondria, characterized by enhanced respiration and energy production, might allow cells to evade DR5-mediated cytotoxicity. Further analysis using clinical datasets demonstrated that the elevated expression of a three-gene signature, consisting of SDHA, IDH3A, and ANXA11, was significantly associated with poor survival of acute leukemia patients. Our analysis therefore provided a unique dataset for a mechanistic understanding of T-ALL and for the design of novel ALL treatments.

A Comprehensive Metabolism-Related Gene Signature Predicts the Survival of Patients with Acute Myeloid Leukemia

“…ENO1 [27][28][29] and PC [31] were found to be overexpressed in several types of AML. A high expression of SDHA [41] and NUP210 [33,34] were positively associated with the unfavorable prognosis of AML patients and an elevated expression of SLC27A4 was linked to poorer clinical outcomes in several cancer types [35]. An upregulated level of SORT1 [37,38] and downregulated INSR [39] were both reported in chemo-resistant or relapsed AML samples.…”

Pathobiological functions and clinical implications of annexin dysregulation in human cancers

“…Moreover, patients harboring high ANXA11 and ANXA4 expression displayed poorer survival than those with low annexin expression ( Duncan et al, 2008 ). High ANXA11 mRNA levels have also been associated to a poor overall survival in patients with acute myeloid leukemia, and related to a resistance mechanism to DR5-targeting agents that induce apoptosis regulation ( Song et al, 2022 ). Since ANXA11 plays a role in apoptosis modulation, it could represent an important player in cancer therapies based on targeting apoptotic pathways and/or the development of resistance mechanisms, and hence emerge as a valuable biomarker to predict treatment response or to identify/stratify the subset of patients who are likely to respond ( Song et al, 2022 ).…”