Reference Detail

Ref Type

Journal Article

PMID

(39033228)

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

PIM1 is a potential therapeutic target for the leukemogenic effects mediated by JAK/STAT pathway mutations in T-ALL/LBL.

Journal	Vol	Issue	Date	Pages	Journal Short Title
NPJ precision oncology	8	1	2024 Jul 20	152	NPJ Precis Oncol

URL

Abstract Text

Precursor T-cell neoplasms (T-ALL/LBL) are aggressive hematological malignancies that arise from the malignant transformation of immature thymocytes. Despite the JAK/STAT pathway is recurrently altered in these neoplasms, there are not pharmacological inhibitors officially approved for the treatment of T-ALL/LBL patients that present oncogenic JAK/STAT pathway mutations. In the effort to identify potential therapeutic targets for those patients, we followed an alternative approach and focused on their transcriptional profile. We combined the analysis of molecular data from T-ALL/LBL patients with the generation of hematopoietic cellular models to reveal that JAK/STAT pathway mutations are associated with an aberrant transcriptional profile. Specifically, we demonstrate that JAK/STAT pathway mutations induce the overexpression of the PIM1 gene. Moreover, we show that the pan-PIM inhibitor, PIM447, significantly reduces the leukemogenesis, as well as the aberrant activation of c-MYC and mTOR pathways in cells expressing different JAK/STAT pathway mutations, becoming a potential therapeutic opportunity for a relevant subset of T-ALL/LBL patients.

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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	LGH447	Preclinical - Cell culture	Actionable	In a preclinical study, LGH447 inhibited viability and proliferation of transformed cells expressing JAK3 Q988P in culture (PMID: 39033228).	39033228