Effects of an Anti-TSLP Antibody on Allergen-Induced Asthmatic Responses

Gauvreau, Gail M.; O'Byrne, Paul M.; Boulet, Louis‐Philippe; Wang, Ying; Cockcroft, Donald W.; Bigler, Jeannette; FitzGerald, J Mark; Boedigheimer, Michael; Davis, Beth E.; Dias, Clapton; Gorski, Kevin; Smith, Lynn; Bautista, Edgar; Comeau, Michael R.; Leigh, Richard; Parnes, Jane R.

doi:10.1056/nejmoa1402895

Cited by 687 publications

(528 citation statements)

References 38 publications

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“…The experimental examination of this hypothesis is challenging, because mouse TSLP is not reactive with the human TSLP receptor (67). The hypothesis suggests that targeting TSLP [for example, by the novel anti-TSLP antibodies (68)] or the TSLP receptor [by for example, CRLF2 antibodies or CAR-T cells (69,70)] may be a useful additional therapy-better than JAK inhibition-to prevent relapse in patients with DS and sporadic CRLF2 pos ALL.…”

Section: Discussionmentioning

confidence: 99%

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Schwartzman

Savino

Gombert

et al. 2017

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

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Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DSALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/ RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2 pos DSALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2 pos , Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.C hildren with Down syndrome (DS) are at a markedly increased risk for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (1). The poor survival of DS-ALL compared with ALL in children without DS ("sporadic" ALL) is related to increased treatment toxicity and to increased incidence of relapse (2). Thus, better therapy is needed for these patients.Previous studies by our group and others revealed differences between the genetics of DS-ALLs and of sporadic ALLs (3-6). The typical cytogenetic subgroups, ETV6-RUNX1 and hyperdiploid ALLs, are less common in DS-ALLs. Acquired somatic activation of the thymic stromal lymphopoietin (TSLP) pathway are present at diagnosis in about half of DS-ALLs. Aberrant expression of cytokine receptor-like factor 2 (CRLF2) in these leukemias is caused by chromosomal rearrangements consisting either of a microdeletion on chromosome X, juxtaposing the promoter of P2RY8 with the coding region of CRLF2, or by a translocation of CRLF2 into the Ig heavy chain (IgH) locus. CRLF2 heterodimerizes with IL7 receptor-α (IL7R) to form the receptor to TSLP (reviewed in ref. 7). TSLP receptors signal by activation of the JAK-STAT pathway. Interestingly, in the majority of DS-ALLs, SignificanceChildren with Down syndrome are at increased risk ...

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Section: Discussionmentioning

confidence: 99%

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Schwartzman

Savino

Gombert

et al. 2017

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

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“…TSLP, in particular, has been proposed to play a key role in eosinophilic asthma. This upstream cytokine has convincingly been shown to be driving classical allergeninduced asthma and eosinophil influx into the airways [87] but is also an important component of the innate type 2 immune system. TSLP plays an important role in the inflammation seen in patients with nasal polyposis [88] and is supposed to contribute to the pathogenesis of aspirin induced asthma [89].…”

Section: Multiple Molecular Pathways Leading To Eosinophilic Airway Imentioning

confidence: 99%

Improving the diagnosis of eosinophilic asthma

Coumou

Bel

2016

Expert Review of Respiratory Medicine

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“…Les corticostéroïdes inhalés, pierre angulaire du traitement de l'asthme persistant [42], non seulement TSLP ou son récepteur [49,50], ou contre le récepteur ST2 de l'IL-33 [51]. La preuve du concept ayant été confirmée chez l'homme pour la TSLP [52], des essais contrôlés devraient confirmer l'intérêt de cibler ces cytokines à l'interface entre l'épithélium et les CD en thérapeutique clinique. [46].…”

Section: Influence Des Traitements Anti-allergiques Sur Les Cellulesunclassified

Les cellules dendritiques humaines dans l’asthme et la rhinite allergique

Froidure

Pilette

2015

Med Sci (Paris)

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Effects of an Anti-TSLP Antibody on Allergen-Induced Asthmatic Responses

Cited by 687 publications

References 38 publications

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Improving the diagnosis of eosinophilic asthma

Les cellules dendritiques humaines dans l’asthme et la rhinite allergique

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