Somatically acquired <i>JAK1</i> mutations in adult acute lymphoblastic leukemia

Flex, Elisabetta; Petrangeli, Valentina; Stella, Lorenzo; Chiaretti, Sabina; Hornakova, Tekla; Knoops, Laurent; Ariola, Cristina; Fodale, Valentina; Clappier, Emmanuelle; Paoloni, Francesca; Martinelli, Simone; Fragale, Alessandra; Sanchez, Massimo; Tavolaro, Simona; Messina, Monica; Cazzaniga, Giovanni; Camera, Andrea; Pizzolo, Giovanni; Tornesello, Assunta; Vignetti, Marco; Battistini, Angela; Cavé, Hélène; Gelb, Bruce D.; Renauld, Jean‐Christophe; Biondi, Andrea; Constantinescu, Stefan N.; Foà, Robin; Tartaglia, Marco

doi:10.1084/jem.20072182

Cited by 313 publications

(290 citation statements)

References 29 publications

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“…46,47 A recent report identified a JAK3 A572V mutation in 1 of 30 MF patients 48 studied. We have found no evidence for the most common activating mutations, JAK1 V658F and JAK2 V617, in primary SS samples.…”

Section: Discussionmentioning

confidence: 99%

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

et al. 2011

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Constitutive and persistent activation of STAT3 has been implicated in the pathogenesis of many malignancies. Studies of CTCL cell lines have previously suggested that aberrant activation of STAT3 is mediated via silencing of the negative regulator SHP-1 by promoter methylation. In this study of ex vivo tumour cell populations from 18 Sé zary syndrome (SS) patients, constitutive phosphorylation of STAT3, JAK1 and JAK2 was present in all patients, but was absent in comparative CD4 þ T-cells from healthy controls. Furthermore, no loss or significant difference in SHP-1 expression was observed between patients and healthy control samples. Methylationspecific PCR analysis of the SHP-1 CpG island in 47 SS patients and 11 healthy controls did not detect any evidence of methylation. Moreover, small interfering RNA knockdown of SHP-1 had no effect on phosphorylation of STAT3. In contrast, treatment of SS tumour cells with the pan-JAK inhibitor pyridone 6 led to downregulation of phosphorylated STAT3 (pSTAT3), its target genes and induction of apoptosis. No evidence for common JAK1/JAK2-activating mutations was found. These data demonstrate that constitutive activation of STAT3 in SS is not due to the loss of SHP-1, but is mediated by constitutive aberrant activation of JAK family members.

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Section: Discussionmentioning

confidence: 99%

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

et al. 2011

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“…Together, these observations suggested that the poor-outcome, IKZF1-deleted, BCR-ABL1-negative cases might harbor activating tyrosine kinase mutations. The JAK-STAT pathway may mediate BCR-ABL1 signaling and transformation (7,8), and JAK1 and JAK2 are mutated in myeloproliferative diseases (9), Down syndrome-associated ALL (DS-ALL), and T lineage ALL (10)(11)(12). Here, we have performed genomic resequencing of JAK1, JAK2, JAK3, and TYK2 in 187 diagnostic samples from this high risk B-progenitor ALL cohort that had available DNA and gene expression profiling data.…”

Section: Ikaros ͉ Kinase ͉ Mutationmentioning

confidence: 99%

JAK mutations in high-risk childhood acute lymphoblastic leukemia

Mullighan

Zhang

Harvey³

et al. 2009

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

513

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Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosomepositive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases JAK1 (n ‫؍‬ 3), JAK2 (n ‫؍‬ 16), and JAK3 (n ‫؍‬ 1) in 20 (10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P ‫؍‬ 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL. IKAROS ͉ kinase ͉ mutationA cute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and despite high overall cure rates (1), ALL remains the second leading cause of cancer death in children. To improve outcome, it is necessary to identify highrisk patients at the time of diagnosis and then tailor therapy toward the genetic lesions driving their leukemia.Recent genome-wide analyses have identified common genetic alterations in childhood ALL that contribute to leukemogenesis (2, 3). To identify genetic lesions predictive of poor outcome in childhood ALL, we recently performed genomewide analysis of DNA copy number alterations, transcriptional profiling, and gene resequencing in a cohort of 221 children with B progenitor ALL predicted to be at high risk for relapse based on age and presentation leukocyte count (4). These patients were treated on the Children's Oncology Group P9906 trial by using an augmented reinduction/reconsolidation strategy (''Berlin-Frankfurt-Münster'' regimen) (5, 6). This cohort excluded patients with known good (ETV6-RUNX1 or trisomies 4 and 10) or very poor (hypodiploid, BCR-ABL1) risk sentinel genetic lesions, and it represents Ϸ12% of noninfant B precursor ALL cases (Table S1). Alteration of the lymphoid transcription factor IKZF1 (IKAROS) was associated with poor outcome and a leukemic cell gene expression signature highly similar to that of BCR-ABL1...

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“…JAK1 pseudokinase mutations have also been described in T-lineage ALL, albeit more commonly in adults than in children. 61,65 The frequency of JAK2 mutations in large cohorts of adult ALL cases has not been determined. Similar to the JAK2 V617F mutation, the JAK1 and JAK2 mutations observed in ALL are transforming in vitro, conferring cytokine-independent growth and constitutive Jak-Stat activation when introduced into Ba/F3 cells (a murine pro-B-cell line) expressing the erythropoietin or thrombopoietin receptors.…”

Section: Genetic Characterization Of Bcr-abl1-like Phà Allmentioning

confidence: 99%