Reference Detail

Ref Type

Journal Article

PMID

(37712558)

Authors

Lahera A, Vela-Martín L, Fernández-Navarro P, Llamas P, López-Lorenzo JL, Cornago J, Santos J, Fernández-Piqueras J, Villa-Morales M

Title

The JAK3Q988P mutation reveals oncogenic potential and resistance to ruxolitinib.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular carcinogenesis	63	1	2024 Jan	5-10	Mol Carcinog

URL

Abstract Text

T-cell acute lymphoblastic leukemia (T-ALL) arises from the malignant transformation of T-cell progenitors at various differentiation stages. Given that patients who relapse have a dismal prognosis, there is an urgent need to identify the molecular alterations that are present in such patients and promote leukemogenesis to implement personalized therapies with higher efficacy and fewer adverse effects. In the present manuscript, we identified the JAK3Q988P mutation in a T-ALL patient who did not achieve a durable response after the conventional treatment and whose tumor cells at relapse presented constitutive activation of the JAK/STAT pathway. Although JAK3Q988P has been previously identified in T-ALL patients from different studies, the functional consequences exerted by this mutation remain unexplored. Through the combination of different hematopoietic cellular models, we functionally characterize JAK3Q988P as an oncogenic mutation that contributes to leukemogenesis. Notably, JAK3Q988P not only promotes constitutive activation of the JAK/STAT pathway in the absence of cytokines and growth factors, as is the case for other JAK3 mutations that have been functionally characterized as oncogenic, but also functions independently of JAK1 and IL2RG, resulting in high oncogenic potential as well as resistance to ruxolitinib. Our results indicate that ruxolitinib may not be efficient for future patients bearing the JAK3Q988P mutation who instead may obtain greater benefits from treatments involving other pharmacological inhibitors such as tofacitinib.

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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

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
JAK3	Q988P	missense	gain of function	JAK3 Q988P lies within protein kinase domain 2 of the Jak3 protein (UniProt.org). Q988P confers a gain of function to the Jak3 protein as demonstrated by constitutive JAK/STAT pathway activation (PMID: 37712558, PMID: 39033228), increased c-Myc and S6 phosphorylation and Pim1 expression (PMID: 39033228), and cytokine-independent growth in culture (PMID: 37712558).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
JAK3 Q988P	hematologic cancer	sensitive	Tofacitinib	Preclinical - Cell culture	Actionable	In a preclinical study, Xeljanz (tofacitinib) inhibited growth of transformed cells expressing JAK3 Q988P in culture (PMID: 37712558).	37712558
JAK3 Q988P	hematologic cancer	decreased response	Ruxolitinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing JAK3 Q988P were less sensitive to Jakafi (ruxolitinib) treatment compared to cells expressing JAK3 M511I in culture (PMID: 37712558).	37712558