Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Leukemia			2022 Apr 11	1499-1507	Leukemia

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
Ritlecitinib	Ritlecitinib	1	1

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
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	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	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	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