ArticleLeukemia2021
MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance.
Article in Leukemia, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03705507 (International Phase I/II Expansion Trial of the MEK Inhibitor Selumetinib in Combination With Dexamethasone for the Treatment of Relapsed/Refractory RAS-pathway Mutated Paediatric and Adult Acute Lymphoblastic Leukaemia), which is not on this map. Cited by 29 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
International Phase I/II Expansion Trial of the MEK Inhibitor Selumetinib in Combination With Dexamethasone for the Treatment of Relapsed/Refractory RAS-pathway Mutated Paediatric and Adult Acute Lymphoblastic Leukaemia
Who cites it
29 citing papers in PubMed, 46 citations in OpenAlex.
- Glucocorticoid resistance-induced inflammation drives cardiovascular-kidney-metabolic (CKM) syndrome pathophysiology.Trends in endocrinology and metabolism: TEM · 2026Review
- The Interleukin-7 Receptor Signaling Pathway and Its Perturbation in Immunodeficiency, Autoimmune Disease and Lymphoid Malignancy.Biomolecules · 2026Review
- Review
- KPT-330, A New Candidate Drug for Targeting NOTCH1 Overexpression in T-cell Acute Lymphoblastic Leukemia, An In Vitro and Silico Study.Cell biochemistry and biophysics · 2025Article
- Promising Drugs Targeting Specific Mechanisms of Deregulation in T Cell Lineage Acute Lymphoblastic Leukemia.Oncology and therapy · 2025Review
- Recent Advances in Signaling Pathways and Kinase Inhibitors for Leukemia Chemotherapy.Current medicinal chemistry · 2025Review
- Multidimensional analysis suggests that ZNF433 is a promising biomarker for the diagnosis and prognosis of human cancers.Frontiers in oncology · 2025Article
- Advances in the application of patient-derived xenograft models in acute leukemia resistance.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Glucocorticoid Therapy in Acute Lymphoblastic Leukemia: Navigating Short-Term and Long-Term Effects and Optimal Regimen Selection.Current hematologic malignancy reports · 2024Review
- The role of the mineralocorticoid receptor in steroidinduced cytotoxicity in pediatric acute lymphoblastic leukemia.Haematologica · 2024Article
- Exploring the relationship between immune heterogeneity characteristic genes of rheumatoid arthritis and acute myeloid leukemia.Discover oncology · 2024Article
- Developing Targeted Therapies for T Cell Acute Lymphoblastic Leukemia/Lymphoma.Current hematologic malignancy reports · 2023Review
- MAPK/ERK and PI3K/AKT signaling pathways are activated in adolescent and adult acute lymphoblastic leukemia.Cancer reports (Hoboken, N.J.) · 2023Article
- JUN mediates glucocorticoid resistance by stabilizing HIF1a in T cell acute lymphoblastic leukemia.iScience · 2023Article
- WDR54 exerts oncogenic roles in T-cell acute lymphoblastic leukemia.Cancer science · 2023Article
- Emerging Epigenetic and Posttranslational Mechanisms Controlling Resistance to Glucocorticoids in Acute Lymphoblastic Leukemia.HemaSphere · 2023Review
- Review
- STAT5 does not drive steroid resistance in T-cell acute lymphoblastic leukemia despite the activation ofHaematologica · 2023Article
- Progress in the studies on the molecular mechanisms associated with multidrug resistance in cancers.Acta pharmaceutica Sinica. B · 2023Review
- Pediatric Acute Lymphoblastic Leukemia Emerging Therapies-From Pathway to Target.International journal of molecular sciences · 2023Review
Corrections and comments
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Authors and funding
18 authors at 6 institutions in 5 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.