Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling.

Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling. Research Abstract Details 

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Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling. Abstract Text:

Valerie I Brown,Jessica Hulitt,Jonathan Fish,Cecilia Sheen,Marlo Bruno,Qing Xu,Martin Carroll,Junjie Fang,David Teachey,Stephan A Grupp,Valerie I Brown,Jessica Hulitt,Jonathan Fish,Cecilia Sheen,Marlo Bruno,Qing Xu,Martin Carroll,Junjie Fang,David Teachey,Stephan A Grupp,

Understanding the pathogenesis of leukemia in the context of lymphopoiesis may reveal novel therapeutic targets. Previously, we have shown that mTOR inhibitors (MTI) show activity in vitro and in preclinical models of both human and murine precursor B acute lymphoblastic leukemia (pre-B ALL), inhibiting cell proliferation and inducing apoptosis. These MTI-mediated effects can be reversed by interleukin-7 (IL-7), an important regulator of early B-cell development. This observation led us to examine the contribution of signaling via the IL-7Ralpha chain, which is shared by the receptor complexes of IL-7 and thymic stromal-derived lymphopoietin (TSLP). TSLP is closely related to IL-7 and active in lymphopoiesis, but an effect of TSLP on leukemia cells has not been described. We examined the effect of TSLP on pre-B ALL cells and their response to MTIs. Here, we show that TSLP stimulates proliferation of pre-B ALL cell lines. TSLP also partially reverses the effects of MTI on proliferation, apoptosis, and ribosomal protein S6 and 4E-BP1 phosphorylation in cell lines, with similar biological effects seen in some primary human lymphoblast samples. These data show that TSLP can promote survival of pre-B ALL cells and antagonize the effects of MTIs. These findings suggest that IL-7Ralpha chain is responsible for transducing the survival signal that overcomes MTI-mediated growth inhibition in pre-B ALL. Thus, further exploration of the IL-7Ralpha pathway may identify potential therapeutic targets in the treatment of ALL. Our data illustrate that growth-factor-mediated signaling may provide one mechanism of MTI resistance.

Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling. Publishing Authors By Initials

VI Brown,J Hulitt,J Fish,C Sheen,M Bruno,Q Xu,M Carroll,J Fang,D Teachey,SA Grupp,VI Brown,J Hulitt,J Fish,C Sheen,M Bruno,Q Xu,M Carroll,J Fang,D Teachey,SA Grupp,

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Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer research

VOLUME: 67

Page Numbers: 9963-70

Journal Abbreviation: Cancer Res.

ISSN: 0008-5472

DAY: 15

MONTH: Oct

YEAR: 2007

Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling. Information

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LANGUAGE: eng

NlmUniqueID: 2984705

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Grant and Affiliation Information for Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling.

AFFILIATION: Division of Oncology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, and Department of Pediatrics, Division of Hematology and Oncology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.

Country: United States

AGENCY: United States NCI

GRANT: R01-CA102646

ACRONYM: CA

MEDLINETA: Cancer Res

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