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Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy
Dongjun Lee, … , Noopur Raje, David T. Scadden
Dongjun Lee, … , Noopur Raje, David T. Scadden
Published February 29, 2016
Citation Information: J Clin Invest. 2016;126(4):1300-1310. https://doi.org/10.1172/JCI84620.
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Research Article Oncology

Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy

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Abstract

Regulation of STAT3 activation is critical for normal and malignant hematopoietic cell proliferation. Here, we have reported that the endogenous transmembrane protein upstream-of-mTORC2 (UT2) negatively regulates activation of STAT3. Specifically, we determined that UT2 interacts directly with GP130 and inhibits phosphorylation of STAT3 on tyrosine 705 (STAT3Y705). This reduces cytokine signaling including IL6 that is implicated in multiple myeloma and other hematopoietic malignancies. Modulation of UT2 resulted in inverse effects on animal survival in myeloma models. Samples from multiple myeloma patients also revealed a decreased copy number of UT2 and decreased expression of UT2 in genomic and transcriptomic analyses, respectively. Together, these studies identify a transmembrane protein that functions to negatively regulate cytokine signaling through GP130 and pSTAT3Y705 and is molecularly and mechanistically distinct from the suppressors of cytokine signaling (SOCS) family of genes. Moreover, this work provides evidence that perturbations of this activation-dampening molecule participate in hematologic malignancies and may serve as a key determinant of multiple myeloma pathophysiology. UT2 is a negative regulator shared across STAT3 and mTORC2 signaling cascades, functioning as a tumor suppressor in hematologic malignancies driven by those pathways.

Authors

Dongjun Lee, Ying-Hua Wang, Demetrios Kalaitzidis, Janani Ramachandran, Homare Eda, David B. Sykes, Noopur Raje, David T. Scadden

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Figure 3

UT2 expression in myeloma cells.

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UT2 expression in myeloma cells.
(A) Copy number of UT2 in solid tumors ...
(A) Copy number of UT2 in solid tumors and hematological cancer cell lines (Broad-Novartis Cancer Cell Line Encyclopedia [n = 338; left panel] and Oncomine database corresponds to GSE20306 data [n = 449] derived from ref. 46 [right panel]). Numbers in parentheses are n values. (B) Copy number of UT2 in primary MM patients were assessed using human genome CGH microarray data obtained from the Oncomine database. Left panel corresponds to GSE26849 data (MGUS [n = 2], MM [n = 249], and plasma cell leukemia [n = 10]) from ref. 56, and right panel corresponds to GSE15695 data (normal donor [n = 84] and MM [n = 84]) from ref. 55. (C) UT2 expression from primary MM patients were assessed using human genome CGH microarray data obtained from the Oncomine database. C panel corresponds to data from refs. 55–59 (GSE2658 data [n = 414], GSE4452 data [n = 65], GSE15695 data [n = 247], GSE26760 data [MGUS (n = 2), MM (n = 299), and plasma cell leukemia (n = 3)], and GSE29023 data [n = 115]). (D) Survival curve relative to UT2 expression (high expression [n = 160] and low expression [n = 382]) in individuals affected by myeloma and based on GSE2658 (58) (log-rank test). (E) Quantitative PCR (qPCR) analyses of UT2 expression in different human control cancer cells and myeloma cells (n = 3 experiments; two-tailed, unpaired t test; **P < 0.01). (F and G) qPCR and Western blots analyses of UT2 expression from primary MM patients. CD138+ myeloma cells and CD138– BM cells were isolated from primary MM patient BM cells, and qPCR analysis (F) (normal donor BM cells [left panel] and CD138– BM fractions [right panel]) and Western blot analysis (G) were performed, respectively. See also Supplemental Figure 3B. Data are shown as mean ± SEM (n = 5–6; two-tailed, unpaired t test; **P < 0.01).

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