Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia.
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.
Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of California-San Francisco, CA 94143, USA.
Sarah K
SK
Tasian
Michelle Y
MY
Doral
Michael J
MJ
Borowitz
Brent L
BL
Wood
I-Ming
IM
Chen
Richard C
RC
Harvey
Julie M
JM
Gastier-Foster
Cheryl L
CL
Willman
Stephen P
SP
Hunger
Charles G
CG
Mullighan
Mignon L
ML
Loh
D000328:Adult; D015153:Blotting, Western; D049109:Cell Proliferation; D002648:Child; D005434:Flow Cytometry; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D019869:Phosphatidylinositol 3-Kinases; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D050799:STAT5 Transcription Factor; D058570:TOR Serine-Threonine Kinases; C498762:CRLF2 protein, human; C546842:MTOR protein, human