Mutant JAK3 signaling is increased by loss of wild-type JAK3 or by acquisition of secondary JAK3 mutations in T-ALL

Degryse, Sandrine; Bornschein, Simon; Bock, Charles E. de; Leroy, Emilie; Bempt, Marlies Vanden; Demeyer, Sofie; Jacobs, Kris; Geerdens, Ellen; Gielen, Olga; Soulier, Jean; Harrison, Christine J.; Constantinescu, Stefan N.; Cools, Jan

doi:10.1182/blood-2017-07-797597

Cited by 32 publications

(52 citation statements)

References 22 publications

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“…23,49,50 Moreover, recent observation in cellular models have shown that wild-type JAK3 competes with the JAK3 mutants that require binding to the gc chain such as JAK3 M511I , JAK3 A572T , and JAK3 A573V , thus suggesting that these mutants are weak. 39 Here, we showed that heterozygous Jak3 KI/WT mice also develop a CTCL phenotype with a longer latency compared with homozygous Jak3 KI/KI . These in vivo results suggest that equal amounts of wild-type JAK3 do not prevent the development of T-cell malignancies.…”

Section: Discussionmentioning

confidence: 66%

“…Of note, Jak3 KI/WT mice displayed a similar expansion of CD8 1 T cells albeit with longer latency (ie, in mice older than age 14 months) (supplemental Figure 3B,G), indicating a dosage effect of the Jak3 mutation on disease development, as has been recently observed in vitro. 39 These results indicate that endogenous expression of Jak3 A572Vactivating mutation induces, progressively and in a dose-dependent manner, a peripheral proliferation of malignant activated effector/ memory CD8 1 T cells with skin involvement closely resembling a leukemic form of human CTCL disorders (L-CTCL).…”

Section: Jak3 Ki/ki Mice Progressively Develop a Ctcl-like Disordermentioning

confidence: 70%

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Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

et al. 2018

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JAK3-activating mutations are commonly seen in chronic or acute hematologic malignancies affecting the myeloid, megakaryocytic, lymphoid, and natural killer (NK) cell compartment. Overexpression models of mutant JAK3 or pharmacologic inhibition of its kinase activity have highlighted the role that these constitutively activated mutants play in the T-cell, NK cell, and megakaryocytic lineages, but to date, the functional impact of JAK3 mutations at an endogenous level remains unknown. Here, we report a JAK3 knockin mouse model and demonstrate that activated JAK3 leads to a progressive and dose-dependent expansion of CD8 T cells in the periphery before colonization of the bone marrow. This phenotype is dependent on the γc chain of cytokine receptors and presents several features of the human leukemic form of cutaneous T-cell lymphoma (L-CTCL), including skin involvements. We also showed that the JAK3-positive malignant cells are transplantable and phenotypically heterogeneous in bone marrow transplantation assays. Interestingly, we revealed that activated JAK3 functionally cooperates with partial trisomy 21 in vivo to enhance the L-CTCL phenotype, ultimately leading to a lethal and fully penetrant disorder. Finally, we assessed the efficacy of JAK3 inhibition and showed that CTCL JAK3-positive T cells are sensitive to tofacitinib, which provides additional preclinical insights into the use of JAK3 inhibitors in these disorders. Altogether, this JAK3 knockin model is a relevant new tool for testing the efficacy of JAK inhibitors in JAK3-related hematopoietic malignancies.

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Section: Discussionmentioning

confidence: 66%

Section: Jak3 Ki/ki Mice Progressively Develop a Ctcl-like Disordermentioning

confidence: 70%

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

et al. 2018

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“…In addition, activating mutations in IL-7 receptor, JAK1, JAK3 , and STAT5 can be found in T-ALL, resulting in activation of JAK-STAT signaling [1,37]. Of note, IL-7 receptor mutations tend to be strongly activating alleles [38,39]; however multiple hits involving JAK1 and JAK3 mutations can be found in the same patient showing cooperative activity in the disease transformation [40]. In this context, inhibition of JAK-STAT can result in antitumor effects in preclinical models [40,41] (Figure 1).…”

Section: Targeting the Jak/stat Pathwaymentioning

confidence: 99%

“…Of note, IL-7 receptor mutations tend to be strongly activating alleles [38,39]; however multiple hits involving JAK1 and JAK3 mutations can be found in the same patient showing cooperative activity in the disease transformation [40]. In this context, inhibition of JAK-STAT can result in antitumor effects in preclinical models [40,41] (Figure 1). Importantly, the antileukemic effects of JAK-STAT inhibition do not seem restricted to leukemias harboring activating mutations in the pathway.…”

Section: Targeting the Jak/stat Pathwaymentioning

confidence: 99%

Can one target T-cell ALL?

Ferrando

2018

Best Practice & Research Clinical Haematology

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Progress in our understanding of the central genes, pathways, and mechanisms in the pathobiology of T-cell acute lymphoblastic leukemia (T-ALL) has identified key drivers of the disease, opening new opportunities for therapy. Drugs targeting highly prevalent genetic alterations in NOTCH1 and CDKN2A are being explored, and multiple other targets with readily available therapeutic agents, and immunotherapies are being investigated. The molecular basis of T-ALL is reviewed here and potential targets and therapeutic targets discussed.

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“…In addition, JAK3 exhibits high level of expression in leukemia ( Fig. S8) and it was found to be frequently mutated in T-cell acute lymphoblastic leukemia 29 . Furthermore, JAK3 was shown to function together with STAT3 to www.nature.com/scientificreports www.nature.com/scientificreports/ Table S1.…”

Section: Potential Roles Of Jak3 In Melanoma Progressionmentioning

confidence: 99%

A Targeted Quantitative Proteomic Method Revealed a Substantial Reprogramming of Kinome during Melanoma Metastasis

Miao

Liu

et al. 2020

Sci Rep

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Kinases are involved in numerous critical cell signaling processes, and dysregulation in kinase signaling is implicated in many types of human cancers. in this study, we applied a parallel-reaction monitoring (pRM)-based targeted proteomic method to assess kinome reprogramming during melanoma metastasis in three pairs of matched primary/metastatic human melanoma cell lines. Around 300 kinases were detected in each pair of cell lines, and the results showed that Janus kinase 3 (JAK3) was with reduced expression in the metastatic lines of all three pairs of melanoma cells. interrogation of The Cancer Genome Atlas (TCGA) data showed that reduced expression of JAK3 is correlated with poorer prognosis in melanoma patients. Additionally, metastatic human melanoma cells/tissues exhibited diminished levels of JAK3 mRNA relative to primary melanoma cells/tissues. Moreover, JAK3 suppresses the migration and invasion of cultured melanoma cells by modulating the activities of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9). In summary, our targeted kinome profiling method provided by far the most comprehensive dataset for kinome reprogramming associated with melanoma progression, which builds a solid foundation for examining the functions of other kinases in melanoma metastasis. Moreover, our results reveal a role of JAK3 as a potential suppressor for melanoma metastasis.

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Mutant JAK3 signaling is increased by loss of wild-type JAK3 or by acquisition of secondary JAK3 mutations in T-ALL

Cited by 32 publications

References 22 publications

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

Partial trisomy 21 contributes to T-cell malignancies induced by JAK3-activating mutations in murine models

Can one target T-cell ALL?

A Targeted Quantitative Proteomic Method Revealed a Substantial Reprogramming of Kinome during Melanoma Metastasis

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