644 Jak3 is essential for common cytokine receptor gamma chain (gc)-dependent signalling: Comparative analysis of gc, Jak3, adn gc and Jak3 double deficient mice

Suzuki, Lisandra Akemi

doi:10.1016/s0091-6749(00)91072-8

Cited by 18 publications

(20 citation statements)

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“…These cytokines are known to be important for efficient lymphopoiesis and for the proper functioning of the different arms of the immune system. 31 Conversely, constitutive activation of JAK3 has been observed in a spectrum of lymphoid malignancies. 12,22 Here, we report that constitutively activated JAK3 in a murine retroviral transduction/BMT model, but not wild-type JAK3, induces a fully penetrant and fatal polyclonal T-cell lymphoproliferative disorder that is transplantable into secondary recipients.…”

Section: Discussionmentioning

confidence: 99%

Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models

Cornejo

Kharas

Werneck

et al. 2009

Blood

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The tyrosine kinase JAK3 plays a wellestablished role during normal lymphocyte development and is constitutively phosphorylated in several lymphoid malignancies. However, its contribution to lymphomagenesis remains elusive. In this study, we used the newly identified activating JAK3A572V mutation to elucidate the effect of constitutive JAK3 signaling on murine lymphopoiesis. In a bone marrow transplantation model, JAK3A572V induces an aggressive, fatal, and transplantable lymphoproliferative disorder characterized by the expansion of IntroductionLymphoid malignancies have been associated with mutations that result in altered function or overexpression in transcription factors, such as NOTCH1, LMO2, or TAL-1/SCL. [1][2][3] Myeloid malignancies are frequently associated with activating alleles of tyrosine kinases, including FLT3ITD or KITD816V in acute myeloid leukemia, 4 BCR-ABL1 in chronic myelogenous leukemia, 5 FIP1L1-PDGFRA in chronic eosinophilic leukemia, 6 TEL-PDGFRB in chronic myelomonocytic leukemia, 7 KITD816V in systemic mastocytosis, 8 and JAK2V617F in the most cases of primary myelofibrosis, polycythemia vera, and essential thrombocythemia. 9 In sharp contrast, only a few mutations in tyrosine kinases have been identified to date in lymphoid malignancies. Examples include fusions involving the anaplastic lymphoma kinase (ALK) gene and different partners, including the nucleophosmin (NPM) gene, which are found in a subset of anaplastic large cell lymphomas (ALCLs), 10 and the fusion between the nuclear pore protein NUP214 and the ABL1 kinase, which is present in approximately 5% of patients with T-cell acute lymphoblastic leukemia (T-ALL). 11 These examples and the frequent activation of downstream effectors of kinases in lymphoma [12][13][14] suggest that other mutations that activate kinases are likely to be found in lymphoid malignancies.The JAK3 tyrosine kinase plays a crucial and unique role in normal lymphocyte development and function. 15,16 JAK3 differs from the other members of the JAK family that include JAK1, JAK2, and TYK2, in several ways. Its expression is developmentally regulated and restricted to the hematopoietic compartment, 17 and it is the only member of the JAK family that interacts with the common gamma chain (␥ c ) of several interleukin receptors, including interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Since these cytokine receptors are necessary for normal lymphopoiesis, loss of JAK3 or ␥ c function results in an early and severe block in T-cell and natural killer (NK) cell development and impaired B-cell function in mice and humans. 18 Collectively, diverse mutations in JAK3 account for approximately 7% to 14% of human severe combined immunodeficiency cases. 19 Conversely, JAK3 activation has been reported in several lymphoproliferative disorders, including mantle-cell lymphoma (MCL), 12 Burkitt lymphoma, 20 HTLV-1-induced adult T-cell lymphoma/leukemia (ATLL), 14 cutaneous T-cell lymphoma (CTCL), 21,22 and anaplastic large-cell lymphoma (ALCL). 23 Interestingly, ...

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Section: Discussionmentioning

confidence: 99%

Constitutive JAK3 activation induces lymphoproliferative syndromes in murine bone marrow transplantation models

Cornejo

Kharas

Werneck

et al. 2009

Blood

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“…JAK3 / mice are viable, although they suffer from severe combined immunodeficiency (Shuai & Liu 2003, Chen et al 2004. This immunological defect is caused by abrogated c-receptor signalling and, since the c-receptor / and JAK3 / phenotypes are identical, it follows that JAK3 is only employed by the short-chain class-I helical cytokines that signal via this common receptor chain (Suzuki et al 2000). JAK2 is employed by all class-I helical cytokines that signal via a homodimeric receptor.…”

Section: Redundancy and Specificity In Helical Cytokine Signallingmentioning

confidence: 99%

Phylogeny and evolution of class-I helical cytokines

Huising¹,

Kruiswijk

Flik³

2006

Journal of Endocrinology

193

136

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The class-I helical cytokines constitute a large group of signalling molecules that play key roles in a plethora of physiological processes including host defence, immune regulation, somatic growth, reproduction, food intake and energy metabolism, regulation of neural growth and many more. Despite little primary amino acid sequence similarity, the view that all contemporary class-I helical cytokines have expanded from a single ancestor is widely accepted, as all class-I helical cytokines share a similar three-dimensional fold, signal via related class-I helical cytokine receptors and activate similar intracellular signalling cascades. Virtually all of our knowledge on class-I helical cytokine signalling derives from research on primate and rodent species. Information on the presence, structure and function of class-I helical cytokines in non-mammalian vertebrates and non-vertebrates is fragmentary. Consequently, our ideas about the evolution of this versatile multigene family are often based on a limited comparison of human and murine orthologs. In the last 5 years, whole genome sequencing projects have yielded draft genomes of the early vertebrates, pufferfish (Takifugu rubripes), spotted green pufferfish (Tetraodon nigroviridis) and zebrafish (Danio rerio). Fuelled by this development, fish orthologs of a number of mammalian class-I helical cytokines have recently been discovered. In this review, we have characterised the mammalian class-I helical cytokine family and compared it with the emerging class-I helical cytokine repertoire of teleost fish. This approach offers important insights into cytokine evolution as it identifies the helical cytokines shared by fish and mammals that, consequently, existed before the divergence of teleosts and tetrapods. A 'fish-mammalian' comparison will identify the class-I helical cytokines that still await discovery in fish or, alternatively, may have been evolutionarily recent additions to the mammalian cytokine repertoire.

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“…IL-7 signals through a heterodimer receptor composed of the IL-7Rα and the γc chains, which are respectively associated to Janus kinase-1 (JAK1) and JAK3 (25,26). Binding of IL-7 to its heterodimer receptor leads to transphosphorylation of JAK1 and JAK3.…”

Section: Introductionmentioning

confidence: 99%