Recurrent mutation of <i>JAK3</i> in T‐cell prolymphocytic leukemia

Bergmann, Anke; Schneppenheim, Sina; Seifert, Marc; Betts, Matthew J.; Haake, Andrea; López, Cristina; Penas, Eva Maria Murga; Vater, Inga; Jayne, Sandrine; Dyer, Martin J. S.; Schrappe, Martin; Dührsen, Ulrich; Ammerpohl, Ole; Russell, Robert B.; Küppers, Ralf; Dürig, Jan; Siebert, Reiner

doi:10.1002/gcc.22141

Cited by 80 publications

(62 citation statements)

References 42 publications

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“…3,4,[8][9][10] Thus, it has been shown that JAK pseudokinase domains are auto-inhibitory and keep the kinase domain inactive until receptor dimerization stimulates transition to an active state. 11 Molecular analysis of deregulated JAK/STAT signaling has provided a novel rationale for treating human cancers using targeted inhibition of JAK kinases.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma

et al. 2015

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Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphomaThe malignant mechanisms that control the development of cutaneous T-cell lymphoma (CTCL) are starting to be identified. Recent evidence suggests that disturbances in specific intracellular signaling pathways, such as RAS-MAPK, TCR-PLCG1-NFAT and JAK-STAT, can play an essential role in the pathogenesis of CTCL.1,2 Our group previously reported a network of somatic mutations affecting genes with potential to affect critical Tcell signaling pathways in CTCL patients. 1 As part of our findings we detected a number of mutations potentially affecting JAK/STAT signaling. These findings were recently confirmed by an independent group, suggesting that mutations in this pathway may contribute as disease mechanisms in CTCL.3 Deregulated JAK/STAT signaling is involved in many types of cancer. In fact, somatically acquired genetic alterations of JAK or STAT genes that induce aberrant activation of downstream signaling, via STAT phosphorylation, have been reported in some human hematologic malignancies including T-cell lymphomas. 4,5 We decided to explore JAK/STAT signaling as part of an intricate network of malignant signaling that controls the pathogenesis of CTCL, on the basis of the following evidence: (i) we had detected mutations in the pseudokinase domain of JAK1 and JAK3 in two of 11 patients and one cell line; (ii) we had also found several mutations that can directly (i.e., IL6S/T) or indirectly (i.e., TRAF6, RELB and CARD11) activate JAK/STAT signaling; and (iii) activated STAT3 had been detected in a large proportion of patients with advanced CTCL. 6,7 To explore the mutational status of JAK genes in a larger cohort of human CTCL patients' samples and cell lines, two independent state-of-the-art ultrasequencing approaches were used: a targeted gene-enrichment kit (HaloPlex) coupled to Ion-PGM (Life Technologies) sequencing, and a specific polymerase chain reactionbased amplification protocol targeting the pseudokinase domains of JAK1, JAK2 and JAK3 genes (hereafter, referred to as PsTKd-PCR), followed by specific indexing and sequencing with MiSeq (Illumina; see the Online Supplementary Methods for details). These are two highly sensitive methods that can enable the detection of mutations even present at low frequencies in neoplastic cells or in minority clones which may be found in CTCL samples. Thus, taken together, the data from our series (including those already described by Vaqué et al. © F e r r a t a S t o r t i F o u n d a t i o nthe pseudokinase domain of JAK proteins, a finding that is consistent with the results of other research groups that have found somatic mutations in the same domain of JAK1 and JAK3 kinases in prolymphocytic leukemia, other T-cell leukemias including CTCL and various human malignancies. 3,4,[8][9][10] Thus, it has been shown that JAK pseudokinase domains are auto-inhibitory and keep the kinase domain inactive until receptor dimerization stimulates transition to an a...

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma

et al. 2015

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“…1 Sequencing studies have identified recurrent mutations in both JAK1 and JAK3 in several hematological malignancies. [2][3][4][5][6][7][8][9][10] We described the importance of JAK3 mutations in the development of T-cell acute lymphoblastic leukemia (T-ALL) and showed that a majority of JAK3 mutants require both binding to the common g chain and presence of JAK1 for their transforming capacities. [11][12][13] However, the JAK3 L857Q/P and L875H kinase domain mutants are exceptions and do not require the common g chain or JAK1 for their transforming capacity.…”

Section: Introductionmentioning

confidence: 99%

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

Degryse

Bornschein

Bock

et al. 2018

Blood

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K E Y P O I N T Sl One-third of T-ALL cases with JAK3 mutation harbor 2 JAK3 mutations.l Double JAK3 mutants show stronger signaling than single JAK3 mutants.The Janus kinase 3 (JAK3) tyrosine kinase is mutated in 10% to 16% of T-cell acute lymphoblastic leukemia (T-ALL) cases. JAK3 mutants induce constitutive JAK/STAT signaling and cause leukemia when expressed in the bone marrow cells of mice. Surprisingly, we observed that one third of JAK3-mutant T-ALL cases harbor 2 JAK3 mutations, some of which are monoallelic and others that are biallelic. Our data suggest that wild-type JAK3 competes with mutant JAK3 (M511I) for binding to the common g chain and thereby suppresses its oncogenic potential. We demonstrate that JAK3 (M511I) can increase its limited oncogenic potential through the acquisition of an additional mutation in the mutant JAK3 allele. These double JAK3 mutants show increased STAT5 activation and increased potential to transform primary mouse pro-T cells to interleukin-7-independent growth and were not affected by wild-type JAK3 expression. These data extend our insight into the oncogenic properties of JAK3 mutations and provide an explanation of why progression of JAK3-mutant T-ALL cases can be associated with the accumulation of additional JAK3 mutations. (Blood. 2018;131(4):421-425)

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“…67 With regards to malignancies of lymphoid lineage, JAK3 mutations were reported in a significant proportion of T-ALL, 68 especially in an aggressive subtype called early T-cell precursor-ALL, 38 as well as in diverse mature Tcell neoplasms. 40,42,[69][70][71] More recently, TYK2 mutants were discovered in T-ALL (21%) and seem to promote cell survival via activation of STAT1 downstream of IL-10R and upregulation of the anti-apoptotic BCL2 protein. …”

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confidence: 99%

JAK kinase targeting in hematologic malignancies: a sinuous pathway from identification of genetic alterations towards clinical indications

2015

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In 2005, several groups reported a unique, acquired, somatic activating mutation of JAK2 (V617F) in 95% of patients with polycythemia vera (PV) and in about half of those with essential thombocythemia (ET) or primary myelofibrosis (MF). [6][7][8][9] The discovery of JAK2 V617F led to screening for JAK mutations in other hematologic neoplasms. Thanks to improvements of sequencing techniques and the conduction of massive sequencing projects, the catalogue of genetic alterations in hematologic malignancies is constantly being updated as ever more new mutational targets are discovered. This review provides an overview of the different molecular mechanisms underlying constitutive activation of the JAK-STAT pathway and their respective frequencies among hematologic neoplasms. The use of JAK inhibitors in the clinic and in ongoing trials, resistance phenomena as well as future challenges are discussed. The review begins by documenting insights into the structural organization of JAK kinases, their mode of activation as well as the role of the different family members in hematopoiesis. Janus kinasesJAK1, JAK2 and TYK2 tyrosine kinases are ubiquitously expressed and non-covalently bound to a distinct, mostly non-overlapping repertory of receptor chains. By contrast, JAK3 expression is restricted to the hematopoietic lineage and it associates exclusively with the common gammachain (γc). Based on their primary sequences, JAK kinases were initially divided into seven highly conserved JAK homology regions (JH1-7, starting from the C-terminal end) but were subsequently organized into four functional domains. 10The N-terminal moiety of JAK kinases constitutes the receptor-binding module with a FERM (band 4.1, ezrin, radixin, moesin) domain (JH4-7) and an atypical SH2 domain (JH3).11 It has been experimentally established that both domains do not exist as individual functional entities but structurally cooperate for non-covalent anchoring to two membrane-proximal regions of defined receptors. 12,13 This was corroborated by a recent crystal structure study showing that the N-terminal part of TYK2 forms a con-JAK kinase targeting in hematologic malignancies haematologica | 2015; 100 (10) 1241 Figure 1. Hematopoiesis. Hematopoiesis originates from a hematopoietic stem cell, which can undergo either self-renewal or hierarchical differentiation into lineage-committed progenitors with decreasing potential that ultimately will give rise to all mature blood cells. Cytokines and their receptor-associated JAK necessary for the progenitors to pass through the different maturation steps are indicated. HSC: hematopoietic stem cell; CMP: common myeloid progenitor; CLP: common lymphoid progenitor; GM: granulocyte macrophage progenitor; BCP: B cell progenitor; TNK: T and natural killer cell progenitor; EP: erythroid progenitor; Mk: megakaryocyte; GP: granulocyte progenitor; MP: macrophage progenitor; TPO: thrombopoietin; SCF: stem cell factor; IL: interleukin; GM-CSF: granulocyte/monocyte colony-stimulating factor; G-CSF: granulocyte c...

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Recurrent mutation of JAK3 in T‐cell prolymphocytic leukemia

Cited by 80 publications

References 42 publications

Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma

Mutated JAK kinases and deregulated STAT activity are potential therapeutic targets in cutaneous T-cell lymphoma

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

JAK kinase targeting in hematologic malignancies: a sinuous pathway from identification of genetic alterations towards clinical indications

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