T-cell Acute Lymphoblastic Leukemia Cells Display Activation of Different Survival Pathways

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a disease of the blood affecting T-lymphocytes. Although notable improvements have been achieved in T-ALL treatment, half of the adult T-ALL patients still experience treatment failure. In order to develop a targeted therapy, we need a better understanding of T-ALL pathogenesis. In this study, we used patient-derived cell lines which display resistance to glucocorticoids. We observed that different cell lines are dependent on different survival signaling pathways. Aberrant activation of AKT, p38, S6K or ERK signaling was not found to the same degree in all cell lines studied. To understand the molecular differences in T-ALL cells, we compared gene expression and somatic mutations. Gene set enrichment analysis showed enrichment of the mTORC1, MAPK or TGF-beta signaling pathways. Loss-of-function mutations in the TP53 and FBXW7 genes were identified in all cell lines investigated. Thus, we suggest that T-ALL cells from different patients are addicted to different mutations and thereby to different signaling pathways. Therefore, understanding the enrichment of molecular pathways for each individual patient will provide us with a more precise and specific treatment plan.

Sinensetin induces apoptosis and autophagy in the treatment of human T-cell lymphoma

“…Despite their similarity, there are several distinct characteristics between these two cell lines. For example, CCRF-CEM cell has lower activation of ERK1/2 than Jurkat cell in response to proliferating stimulations, although they both harbor KRAS mutations [34]. Moreover, the addition of mitogens, such as phorbol 12-myristate 13-acetate (TPA), induces strong cell proliferation and activation in Jurkat cells, whereas CCRF-CEM cells poorly respond to this kind of stimulations [35].…”

Prognostic relevance of genetic variations in T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma

“…After the notch intracellular domain (NICD) is released, it binds to the transcribed regions of genes such as c-MYC, HES1, and NF-κB and plays its role. Mutation of NOTCH1 mainly affects two domains, the extracellular heterodimerization domain (HD) and proline-glutamic acid-serinethreonine (PEST) domain, which can lead to non-liganddependent activation of transmembrane receptors and abnormal activation of downstream genes (15)(16)(17)(18). The Notch signaling pathway plays a key role in regulating development and differentiation via diverse cellular processes, such as differentiation, proliferation, apoptosis, adhesion, cell cycle progression, spatial development, and stem cell maintenance and self-renewal, as well as in the normal development of many tissues and organs.…”

“…Although the mutation frequency of FBXW7 is less than 15% in T-ALL patients ( 16 ), FBXW7 has been considered a candidate prognostic marker in association with NOTCH1 mutation ( 18 , 29 ). Numerous studies have been conducted and found that the prognosis of T-ALL patients with FBXW7 mutation is more favorable than that of patients without FBXW7 mutation ( 13 , 29 , 30 ).…”

mTOR inhibition downregulates glucose-6-phosphate dehydrogenase and induces ROS-dependent death in T-cell acute lymphoblastic leukemia cells

“…T-ALL cells often present activation of the mechanistic target of rapamycin (mTOR) pathway [ [10] , [11] , [12] , [13] ], a key cellular hub connecting nutrient availability and energy sensing, cell growth and survival pathways [ 14 ]. Elevated expression of the MTOR gene (coding for mTOR, a serine/threonine kinase that is key to the pathway) is correlated with failure of T-ALL patients to respond to induction chemotherapy [ 15 ].…”