Abstract
The discovery of gene fusion mutations, particularly in leukemia, has consistently identified new cancer pathways and led to molecular diagnostic assays and molecular-targeted chemotherapies for cancer patients. Here, we report our discovery of a novel CREB3L2-PPARgamma fusion mutation in thyroid carcinoma with t(3;7)(p25;q34), showing that a family of somatic PPARgamma fusion mutations exist in thyroid cancer. The CREB3L2-PPARgamma fusion encodes a CREB3L2-PPARgamma fusion protein that is composed of the transactivation domain of CREB3L2 and all functional domains of PPARgamma1. CREB3L2-PPARgamma was detected in <3% of thyroid follicular carcinomas. Engineered overexpression of CREB3L2-PPARgamma induced proliferation by 40% to 45% in primary human thyroid cells, consistent with a dominant oncogenic mechanism. Wild-type CREB3L2 was expressed in the thyroid as a bZIP transcription factor with a transmembrane domain that has flanking S1P and S2P proteolytic cleavage sites. Native CREB3L2 was cleaved to nuclear CREB3L2 by regulated intramembrane proteolysis in normal thyroid cells that expressed the S1P and S2P proteases. Nuclear CREB3L2 stimulated transcription 8-fold from the EVX1 cyclic AMP (cAMP) response element in the absence of cAMP, whereas CREB3L2-PPARgamma inhibited transcription 6-fold from EVX1 in the same experiments. CREB3L2-PPARgamma also inhibited 4-fold the expression of thyroglobulin, a native cAMP-responsive gene, in primary thyroid cells treated with thyroid-stimulating hormone. Our findings identify a novel CREB3L2-PPARgamma gene fusion mutation in thyroid carcinoma and reveal a thyroid signaling pathway that is regulated by intramembrane proteolysis and disrupted in cancer.
Highlights
Gene fusion mutations underlie a significant subset of human cancers
Our experiments show that the encoded CREB3-like 2 (CREB3L2)-PPARg fusion protein stimulates proliferation and inhibits cyclic AMP (cAMP)-responsive transcription in normal thyroid cells treated with thyroid-stimulating hormone (TSH)
Dualcolor Fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) probes that flank CREB3L2 (22G20, 351B12, 29B3, 83I11, and 691P5) confirmed CREB3L2 rearrangement in paraffin-embedded thyroid carcinomas with t(3;7) (Fig. 1C). These experiments showed that both CREB3L2 and PPARc are rearranged in thyroid carcinoma with t(3;7)
Summary
Scientific investigations of gene fusions, in leukemia, have led to (a) the identification of biological pathways that are deregulated in many cancer types; (b) the development of specific molecular diagnostic assays that identify and monitor. Families of gene fusions tend to characterize specific cancer types. The RUNX1-ETO and CBFb-SMMHC gene fusions underlie acute myeloid leukemia and deregulate the RUNX/ CBFh transcription factor complex by distinct molecular mechanisms [4]. The PML-RARa, PLZF-RARa, NPMRARa, NuMA-RARa , and Stat5b-RARa gene fusions underlie acute promyelocytic leukemia. The low incidence gene fusions have revealed molecular mechanisms that were unapparent from investigation of PML-RARa alone [5, 6] and have identified biological pathways that are important in both acute promyelocytic leukemia and other cancer types
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