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Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia.
Blood 2012; 120(4):833-42Blood

Abstract

Adults and children with high-risk CRLF2-rearranged acute lymphoblastic leukemia (ALL) respond poorly to current cytotoxic chemotherapy and suffer unacceptably high rates of relapse, supporting the need to use alternative therapies. CRLF2 encodes the thymic stromal lymphopoietin (TSLP) receptor, which activates cell signaling in normal lymphocytes on binding its ligand, TSLP. We hypothesized that aberrant cell signaling occurs in CRLF2-rearranged ALL and can be targeted by signal transduction inhibitors of this pathway. In a large number of primary CRLF2-rearranged ALL samples, we observed increased basal levels of pJAK2, pSTAT5, and pS6. We thus characterized the biochemical sequelae of CRLF2 and JAK alterations in CRLF2-rearranged ALL primary patient samples via analysis of TSLP-mediated signal transduction. TSLP stimulation of these leukemias further induced robust JAK/STAT and PI3K/mTOR pathway signaling. JAK inhibition abrogated phosphorylation of JAK/STAT and, surprisingly, of PI3K/mTOR pathway members, suggesting an interconnection between these signaling networks and providing a rationale for testing JAK inhibitors in clinical trials. The PI3K/mTOR pathway inhibitors rapamycin, PI103, and PP242 also inhibited activated signal transduction and translational machinery proteins of the PI3K/mTOR pathway, suggesting that signal transduction inhibitors targeting this pathway also may have therapeutic relevance for patients with CRLF2-rearranged ALL and merit further preclinical testing.

Authors+Show Affiliations

Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California-San Francisco, CA 94143, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22685175

Citation

Tasian, Sarah K., et al. "Aberrant STAT5 and PI3K/mTOR Pathway Signaling Occurs in Human CRLF2-rearranged B-precursor Acute Lymphoblastic Leukemia." Blood, vol. 120, no. 4, 2012, pp. 833-42.
Tasian SK, Doral MY, Borowitz MJ, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood. 2012;120(4):833-42.
Tasian, S. K., Doral, M. Y., Borowitz, M. J., Wood, B. L., Chen, I. M., Harvey, R. C., ... Loh, M. L. (2012). Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood, 120(4), pp. 833-42. doi:10.1182/blood-2011-12-389932.
Tasian SK, et al. Aberrant STAT5 and PI3K/mTOR Pathway Signaling Occurs in Human CRLF2-rearranged B-precursor Acute Lymphoblastic Leukemia. Blood. 2012 Jul 26;120(4):833-42. PubMed PMID: 22685175.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. AU - Tasian,Sarah K, AU - Doral,Michelle Y, AU - Borowitz,Michael J, AU - Wood,Brent L, AU - Chen,I-Ming, AU - Harvey,Richard C, AU - Gastier-Foster,Julie M, AU - Willman,Cheryl L, AU - Hunger,Stephen P, AU - Mullighan,Charles G, AU - Loh,Mignon L, Y1 - 2012/06/08/ PY - 2012/6/12/entrez PY - 2012/6/12/pubmed PY - 2012/10/10/medline SP - 833 EP - 42 JF - Blood JO - Blood VL - 120 IS - 4 N2 - Adults and children with high-risk CRLF2-rearranged acute lymphoblastic leukemia (ALL) respond poorly to current cytotoxic chemotherapy and suffer unacceptably high rates of relapse, supporting the need to use alternative therapies. CRLF2 encodes the thymic stromal lymphopoietin (TSLP) receptor, which activates cell signaling in normal lymphocytes on binding its ligand, TSLP. We hypothesized that aberrant cell signaling occurs in CRLF2-rearranged ALL and can be targeted by signal transduction inhibitors of this pathway. In a large number of primary CRLF2-rearranged ALL samples, we observed increased basal levels of pJAK2, pSTAT5, and pS6. We thus characterized the biochemical sequelae of CRLF2 and JAK alterations in CRLF2-rearranged ALL primary patient samples via analysis of TSLP-mediated signal transduction. TSLP stimulation of these leukemias further induced robust JAK/STAT and PI3K/mTOR pathway signaling. JAK inhibition abrogated phosphorylation of JAK/STAT and, surprisingly, of PI3K/mTOR pathway members, suggesting an interconnection between these signaling networks and providing a rationale for testing JAK inhibitors in clinical trials. The PI3K/mTOR pathway inhibitors rapamycin, PI103, and PP242 also inhibited activated signal transduction and translational machinery proteins of the PI3K/mTOR pathway, suggesting that signal transduction inhibitors targeting this pathway also may have therapeutic relevance for patients with CRLF2-rearranged ALL and merit further preclinical testing. SN - 1528-0020 UR - https://www.unboundmedicine.com/medline/citation/22685175/Aberrant_STAT5_and_PI3K/mTOR_pathway_signaling_occurs_in_human_CRLF2_rearranged_B_precursor_acute_lymphoblastic_leukemia_ L2 - http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=22685175 DB - PRIME DP - Unbound Medicine ER -