MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance

Abstract

Patho-)physiological activation of the IL7-receptor (IL7R) signaling contributes to steroid resistance in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Here, we show that activating IL7R pathway mutations and physiological IL7R signaling activate MAPK-ERK signaling, which provokes steroid resistance by phosphorylation of BIM. By mass spectrometry, we demonstrate that phosphorylated BIM is impaired in binding to BCL2, BCLXL and MCL1, shifting the apoptotic balance toward survival. Treatment with MEK inhibitors abolishes this inactivating phosphorylation of BIM and restores its interaction with anti-apoptotic BCL2-protein family members. Importantly, the MEK inhibitor selumetinib synergizes with steroids in both IL7-dependent and IL7-independent steroid resistant pediatric T-ALL PDX samples. Despite the anti-MAPK-ERK activity of ruxolitinib in IL7-induced signaling and JAK1 mutant cells, ruxolitinib only synergizes with steroid treatment in IL7-dependent steroid resistant PDX samples but not in IL7-independent steroid resistant PDX samples. Our study highlights the central role for MAPK-ERK signaling in steroid resistance in T-ALL patients, and demonstrates the broader application of MEK inhibitors over ruxolitinib to resensitize steroid-resistant T-ALL cells. These findings strongly support the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507) and contributes to the optimization and stratification of newly designed T-ALL treatment regimens.

Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

“…Interestingly, in those samples, MAPK-ERK signaling was activated by IL-7, indicating that physiological IL-7 signaling may activate the downstream MAPK-ERK pathway in T-ALL. Thus, in T leukemic cells, MAPK-ERK can be upregulated both by mutant and physiological IL-7 signaling [ 118 ]. Interestingly, the MAPK-ERK signaling pathway is not activated by the IL-7 signaling in the healthy T-cells [ 119 ].…”

“…Therefore, ruxolitinib has limited clinical application, as it may efficiently decrease MAPK-ERK activation caused by IL-7R/JAK mutations or physiological IL-7 transmission, whereas it is not useful in the alterations occurring downstream of IL-7R/JAK. Such limitations are not encountered when using MAPK inhibitors [ 118 ].…”

“…Inhibiting the JAK/STAT pathway, combined with blocking MAPK/ERK signaling, seems to be a rational strategy. MAPK/ERK can be also activated by Ras -activating mutations, therefore blocking JAK/STAT signaling may not be enough to overcome resistance to the treatment [ 118 , 119 , 120 , 121 , 122 , 123 ]. Furthermore, combining JAK/STAT inhibitors with Bcl-2 inhibitors is also rational, as STAT proteins induce Bcl-2.…”

Metabolic Reprogramming and Cell Adhesion in Acute Leukemia Adaptation to the CNS Niche

“…Growing evidence suggests the crucial role of intrinsic and extrinsic factors in modulating leukemic cell survival (Silva et al, 2011;Giambra et al, 2015;Pitt et al, 2015;Moharram et al, 2017;Ribeiro et al, 2018;van der Zwet et al, 2021). Leukemic cells remain in a quiescent state and highly depend on intrinsic survival factors while circulating in the blood (Guan et al, 2003).…”

STAT5 does not drive steroid resistance in T-cell acute lymphoblastic leukemia despite the activation of <i>BCL2</i> and <i>BCLXL</i> following glucocorticoid treatment

“…Recently, the mechanisms underlying IL7R-dependent survival and/or steroid resistance have been studied. IL7R signaling results in downstream activation of the PI3K-AKT and STAT5 pathways, but also activates MAPK-ERK signaling (6,(8)(9)(10)(11)(12). For these individual downstream signaling pathways, different mechanisms have been identified that may contribute to steroid resistance (Figure 1).…”