Janus Kinase Deregulation in Leukemia and Lymphoma

Chen, Edwin; Staudt, Louis M.; Green, Anthony

doi:10.1016/j.immuni.2012.03.017

Cited by 117 publications

(135 citation statements)

References 120 publications

(141 reference statements)

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“…Recent cancer genome sequencing studies have shown that assorted mutations in JAK1, JAK2, and JAK3 can also induce myeloid neoplasias as well as a smaller number of solid tumors (16,17). Most of these mutations cluster in and around the N-lobe of the pseudokinase domain near the JAK2 V617F mutation, with a smaller subset in the N-lobe of the kinase domain.…”

Section: Jak1 | Jak3mentioning

confidence: 99%

“…Although JAK kinase inhibition has proven to be an attractive drug target for a number of immune indications (15), the discovery of the JAK2 V617F mutation as causative for polycythemia vera and other myeloproliferative neoplasms (MPNs) has prompted the investigation of all JAK family members in a number of malignancies (16). Recent cancer genome sequencing studies have shown that assorted mutations in JAK1, JAK2, and JAK3 can also induce myeloid neoplasias as well as a smaller number of solid tumors (16,17).…”

Section: Jak1 | Jak3mentioning

confidence: 99%

See 1 more Smart Citation

Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Lupardus¹,

Ultsch²,

Wallweber³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

192

241

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Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase-kinase module from the JAK family member TYK2 in its autoinhibited form. We find that the pseudokinase and kinase interact near the kinase active site and that most reported mutations in cancer-associated JAK alleles cluster in or near this interface. Mutation of residues near the TYK2 interface that are analogous to those in cancer-associated JAK alleles, including the V617F and "exon 12" JAK2 mutations, results in increased kinase activity in vitro. These data indicate that JAK pseudokinases are autoinhibitory domains that hold the kinase domain inactive until receptor dimerization stimulates transition to an active state. JAK1 | JAK3H elical bundle cytokines of the interleukin and IFN families regulate a wide variety of immune and cellular growth responses (1). These signaling pathways are initiated by cytokinemediated receptor dimerization and subsequent activation of nonreceptor tyrosine kinases called Janus kinases (JAKs) that are associated with the receptor intracellular domains (2). JAK activation leads to phosphorylation of the receptor and recruitment of STAT family transcription factors, which are then phosphorylated by the JAK and translocated to the nucleus where they induce gene transcription. The JAK family consists of four members (JAK1, JAK2, JAK3, and tyrosine kinase 2 or TYK2), each of which binds a distinct set of cytokine receptor subtypes and hence has a unique gene knockout phenotype, ranging from embryonic lethality due to neuronal and erythropoietic defects (JAK1 and JAK2, respectively) (3-5), to profound immune system deficiencies (JAK3 and TYK2) (6).The JAK kinases are large (∼1,150-aa) multidomain proteins whose primary sequences were initially organized into seven JAK-homology (JH) domains that reflected distinct regions of high sequence homology (7). Subsequent structure predictions indicated that JAKs contain four distinct domains: N-terminal 4.1, Ezrin, Radixin, Moesin (FERM) and Src homology 2 (SH2) domains, followed by C-terminal pseudokinase and kinase domains (7,8) (Fig. 1A). The FERM and SH2 domains constitute the receptor-binding module (2), whereas the pseudokinase, which has a canonical kinase fold but lacks key catalytic residues, is thought to regulate kinase activity. Deletion of the pseudokinase in JAK2 and JAK3 increases basal kinase activity and deregulates signaling through cognate receptors (9, 10). Additionally, the JAK2 pseudokinase and kinase domains have been reported to coimmunoprecipitate, and coexpression of the JAK2 pseudokinase domain inhibits activity of the isolated kinase domain (10). Recent work on the JAK2 pseudokinase domain indicates that it has weak catalytic activity and autophosphorylates two inhibitory sites within the SH2-pseudokinase linker and pseudokinase...

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Section: Jak1 | Jak3mentioning

confidence: 99%

Section: Jak1 | Jak3mentioning

confidence: 99%

Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Lupardus¹,

Ultsch²,

Wallweber³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

192

241

View full text Add to dashboard Cite

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“…After cytokine binding to these receptors, JAKs undergo tyrosine phosphorylation and initiate the phosphorylation of STAT proteins, which translocate to the nucleus and initiate gene transcription. 8 JAK phosphorylation has also been shown to activate other important pathways such as PI3K, RAS, AKT and MAPK. JAK proteins thus play a pivotal role in many cellular functions such as cell growth, differentiation and survival, and activating mutations of these kinases have been associated with malignant transformation.…”

Section: Introductionmentioning

confidence: 99%

“…JAK proteins thus play a pivotal role in many cellular functions such as cell growth, differentiation and survival, and activating mutations of these kinases have been associated with malignant transformation. [8][9][10] Since JAK gene silencing had not previously been associated with tumor cell susceptibility to immune attack, we undertook a series of experiments to understand the mechanisms whereby JAK1 and JAK2 modulate tumor susceptibility to NK cells. Because JAK1 and JAK2 signal through the IFNg receptor, we focused on the potential role of IFNg when NK cells interact with tumor cell targets.…”

Section: Introductionmentioning

confidence: 99%

Interferon-γ-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression

et al. 2015

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“…Genetic alterations affecting members of the Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) were discovered in a variety of T-cell malignancies (1,2). Furthermore, increases in the common γc cytokine concentrations that signal through the JAK1/3, STAT3/5 pathway have been demonstrated in angioimmunoblastic T-cell lymphoma, gamma delta T-cell lymphoma, and adult T-cell leukemia (ATL), thereby identifying effective therapeutic targets.…”

mentioning

confidence: 99%

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

Zhang

Griner

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1-encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokinedependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients' PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL.adult T-cell leukemia | Janus kinase | ruxolitinib | navitoclax T -cell leukemia/lymphoma represents ∼10% of lymphoid malignancies. Genetic alterations affecting members of the Janus kinases (JAKs) and signal transducers and activators of transcription (STAT) were discovered in a variety of T-cell malignancies (1, 2). Furthermore, increases in the common γc cytokine concentrations that signal through the JAK1/3, STAT3/5 pathway have been demonstrated in angioimmunoblastic T-cell lymphoma, gamma delta T-cell lymphoma, and adult T-cell leukemia (ATL), thereby identifying effective therapeutic targets.ATL is an aggressive T-cell malignancy characterized by the clonal expansion of CD4 + CD25 + T lymphocytes that develops in a small proportion of individuals infected with human T-cell lymphotrophic virus-1 (HTLV-1) (3-5). Clinically, ATL is subclassified into four subtypes: smoldering, chronic, lymphomatous, and acute (4, 5). Presently, there is no curative therapy for ATL (4, 5). In search of effective therapies, we examined key signaling pathways that confer a proliferation and viability advantage to ATL cells. It was noted that the HTLV-1-encoded Tax (transactivator from the X-gene region) is associated with increased Bcl-xL (B-cell lymphoma-extra large) expression in ATL cells (6). Furthermore, we reported two autocrine loops (IL-2/IL-2Rα, IL-15/IL-15Rα) and one paracrine loop that in...

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Janus Kinase Deregulation in Leukemia and Lymphoma

Cited by 117 publications

References 120 publications

Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Structure of the pseudokinase–kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition

Interferon-γ-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

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