Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia

Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California-San Francisco, CA 94143, USA.
Blood (Impact Factor: 10.45). 06/2012; 120(4):833-42. DOI: 10.1182/blood-2011-12-389932
Source: PubMed


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.

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Available from: Charles G Mullighan
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    • "CRLF2 rearrangements result in constitutive activation of the STAT5 pathway, resulting in leukemogenesis. Additionally, abnormal PI3K/mTOR pathway signaling has also been implicated [87]. "
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    • "Initial studies using (non-CRLF2-rearranged) murine B-ALL models identified activation of PI3K/mTOR signaling in these leukemias, which was modulated by IL-7 and TSLP and could be abrogated in vitro and in vivo by sirolimus treatment (24, 25). Subsequently, constitutive activation of both JAK/STAT and PI3K/mTOR signaling was reported specifically in in vitro analyses of primary pediatric ALL specimens with JAK mutations and/or CRLF2 rearrangements (19). Aberrant signaling was abrogated in vitro with co-incubation of ALL cells with TKIs, including the JAK inhibitor ruxolitinib and various inhibitors of the PI3K/mTOR pathway (19). "
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    • "The high-confidence reactions were filtered using the criteria described previously by our group (35). The directionality of molecular reactions were devised based on TSLP-induced signaling studies (for instance from studies that use inhibition assays) (17, 40, 54). The pathway map was made using PathVisio, a freely available pathway drawing software (55). "
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