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Ref Type Journal Article
PMID (35411095)
Authors Bodaar K, Yamagata N, Barthe A, Landrigan J, Chonghaile TN, Burns M, Stevenson KE, Devidas M, Loh ML, Hunger SP, Wood B, Silverman LB, Teachey DT, Meijerink JP, Letai A, Gutierrez A
Title JAK3 mutations and mitochondrial apoptosis resistance in T-cell acute lymphoblastic leukemia.
Journal Leukemia
Vol
Issue
Date 2022 Apr 11
URL
Abstract Text Resistance to mitochondrial apoptosis predicts inferior treatment outcomes in patients with diverse tumor types, including T-cell acute lymphoblastic leukemia (T-ALL). However, the genetic basis for variability in this mitochondrial apoptotic phenotype is poorly understood, preventing its rational therapeutic targeting. Using BH3 profiling and exon sequencing analysis of childhood T-ALL clinical specimens, we found that mitochondrial apoptosis resistance was most strongly associated with activating mutations of JAK3. Mutant JAK3 directly repressed apoptosis in leukemia cells, because its inhibition with mechanistically distinct pharmacologic inhibitors resulted in reversal of mitochondrial apoptotic blockade. Inhibition of JAK3 led to loss of MEK, ERK and BCL2 phosphorylation, and BH3 profiling revealed that JAK3-mutant primary T-ALL patient samples were characterized by a dependence on BCL2. Treatment of JAK3-mutant T-ALL cells with the JAK3 inhibitor tofacitinib in combination with a spectrum of conventional chemotherapeutics revealed synergy with glucocorticoids, in vitro and in vivo. These findings thus provide key insights into the molecular genetics of mitochondrial apoptosis resistance in childhood T-ALL, and a compelling rationale for a clinical trial of JAK3 inhibitors in combination with glucocorticoids for patients with JAK3-mutant T-ALL.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Ritlecitinib PF-06651600|PF06651600|PF 06651600 JAK3 Inhibitor 6 Ritlecitinib (PF-06651600) is a covalent Jak3 inhibitor, which reduces downstream signaling and potentially inhibits tumor cell viability (PMID: 35411095).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
JAK3 L857P missense gain of function JAK3 L857P lies within protein kinase domain 2 of the Jak3 protein (UniProt.org). L857P results in cytokine receptor complex-independent activation of Jak3, increased cell proliferation (PMID: 26446793), and cytokine-independent growth in culture (PMID: 35411095).
JAK3 R549Q missense gain of function - predicted JAK3 R549Q lies within protein kinase domain 1 of the Jak3 protein (UniProt.org). R549Q results in cytokine-independent growth in culture (PMID: 35411095), and therefore, is predicted to lead to a gain of Jak3 protein function.
JAK3 R887C missense gain of function - predicted JAK3 R887C lies within protein kinase domain 2 of the Jak3 protein (UniProt.org). R887C results in cytokine-independent growth in cell culture (PMID: 35411095), and therefore, is predicted to lead to a gain of Jak3 protein function.
JAK3 V674A missense gain of function JAK3 V674A lies within protein kinase domain 1 of the Jak3 protein (UniProt.org). V674A confers a gain of function on the Jak3 protein as demonstrated by increased kinase activity (PMID: 16790275, PMID: 20400977) and the ability to transform cells in culture (PMID: 16790275, PMID: 20400977, PMID: 35411095).
JAK3 V678M missense gain of function JAK3 V678M lies within protein kinase domain 1 of the Jak3 protein (UniProt.org). V678M results in constitutive phosphorylation of Jak3, activation of Stat5 and Erk signaling (PMID: 25193870), and is transforming in cell culture (PMID: 25193870, PMID: 35411095).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK3 M511I T-cell acute lymphoblastic leukemia sensitive Tofacitinib Preclinical - Patient cell culture Actionable In a preclinical study, Xeljanz (tofacitinib) treatment inhibited downstream signaling, induced apoptosis, and reduced cell viability of patient-derived T-cell acute lymphoblastic leukemia cell lines harboring JAK3 M511I (PMID: 35411095). 35411095
JAK3 M511I T-cell acute lymphoblastic leukemia sensitive Ritlecitinib Preclinical - Patient cell culture Actionable In a preclinical study, Ritlecitinib (PF-06651600) treatment inhibited downstream signaling, induced apoptosis, and reduced cell viability of patient-derived T-cell acute lymphoblastic leukemia cell lines harboring JAK3 M511I (PMID: 35411095). 35411095
JAK3 M511I T-cell acute lymphoblastic leukemia sensitive Dexamethasone + Tofacitinib Preclinical - Pdx & cell culture Actionable In a preclinical study, Xeljanx (tofacitinib) and Adexone (dexamethasone) combination treatment increased apoptosis and synergistically reduced viability of a patient-derived T-cell acute lymphoblastic leukemia cell line harboring JAK3 M511I in culture and resulted in reduced leukemic burden in a patient-derived xenograft (PDX) model compared to either drug alone (PMID: 35411095). 35411095
JAK3 M511I T-cell acute lymphoblastic leukemia sensitive Selumetinib Preclinical - Patient cell culture Actionable In a preclinical study, Koselugo (selumetinib) treatment induced apoptosis and reduced cell viability of patient-derived T-cell acute lymphoblastic leukemia cell lines harboring JAK3 M511I (PMID: 35411095). 35411095