Two Key Factors Control The Mammary Stem Cell State

2012 Cancer Discovery  
reSearCh watCh Analysis of global transcriptional networks has the potential to decipher oncogenic regulatory circuits and provide insight into the underlying blologic mechanisms that drive disease. Della Gatta and colleagues interrogated the effects of 2 transcription factors frequently activated by chromosomal translocations in T-cell acute lymphoblastic leukemia (T-ALL): T-cell leukemia homeobox 1 and 3 (TLX1 and TLX3, also known as HOX11 and HOX11L2, respectively). Analysis of T-ALL gene
more » ... ression data revealed that TLX1-or TLX3-expressing tumors share a common transcriptional signature that is distinct from that of other T-ALLs. Using a computational approach that inferred a T-ALL interactome from the gene expression data of 228 tumors, the authors identified runt-related transcription factor 1 (RUNX1) as the most interconnected gene in the subnetwork of genes directly regulated by TLX1 and TLX3. Loss of RUNX1 expression may contribute to the oncogenic effects of TLX1 and TLX3 expression, as Runx1 was one of the most significantly downregulated genes in a mouse model of Tlx1-induced T-ALL, RUNX1 target genes were highly enriched among the most downregulated transcripts in human T-ALLs expressing high levels of TLX1 or TLX3, and forced expression of RUNX1 impaired the growth of TLX1-and TLX3-positive T-ALL cells. Consistent with these data implicating RUNX1 inactivation in the pathogenesis of T-ALL, recurrent truncating and missense RUNX1 mutations were identified in human T-ALLs that clustered near the DNA recognition interface of RUNX1 and led to diminished transactivation of a RUNX1-responsive reporter construct. Together, these findings implicate RUNX1 as a tumor suppressor in T-ALL and highlight the power of network-based approaches to identify genes and pathways that drive tumorigenesis. ≠ Della Gatta G, Palomero T, Perez-Garcia A, Ambesi-Impiombato A, Bansal M, Carpenter ZW, et al. Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL. Nat Med 2012;18:436-40. RUNX1 Is a tUMOR sUPPRessOR IN t-aLL Major finding: TLX oncogenic effects are mediated by RUNX1 downregulation. approach: RUNX1 was a major hub in a network of genes regulated by TLX1/3 in T-ALL. Impact: RUNX1 is a master regulator of TLX-dependent transcriptional programs. Leukemia distinct genetic program that was required for MaSC formation and continued to maintain the MaSC state even after the expression of each factor was silenced. These factors also were shown to regulate human breast cancer SCs, as SLUG and SOX9 overexpression in nonmetastatic breast cancer cells converted them into metastasis-seeding cells. In addition, high expression levels of both SLUG and SOX9 were associated with poor outcome in patients with breast cancer. This study not only identifies a conserved and clinically relevant MaSC regulatory network but also provides insight into the genetic programs that potentially determine the SC state of other types of adult epithelial cells. ≠ Guo W, Keckesova Z, Liu Donaher J, Shibue T, Tischler V, Reinhardt F, et al. Slug and Sox9 cooperatively determine the mammary stem cell state. Cell 2012;148:1015-28. Master transcription regulatory networks have been shown to play a role in the establishment of the embryonic stem cell (SC) state. However, the factors that control adult SC programs have not yet been defined. Guo and colleagues identified SLUG and SOX9 to be the key transcription factors that cooperatively regulate the mammary SC (MaSC) state. The authors first found enriched expression of SLUG, a transcription factor implicated in the epithelial-mesenchymal transition, in murine MaSCs. SOX9 was then identified in a screen for factors that acted cooperatively with SLUG to establish the MaSC state. Transient coexpression of SOX9 and SLUG in mammary epithelial cells was sufficient to induce the formation of self-renewing MaSCs capable of long-term mammary gland repopulation, and knockdown of either factor abrogated this activity. Using gene expression analyses, the authors confirmed that SLUG and SOX9 each activated a Major finding: Mammary stem cell formation is regulated by SLUG and SOX9. Concept: SLUG and SOX9 activate distinct but cooperative genetic networks. Impact: A master regulator program maintains the adult stem cell state.
doi:10.1158/2159-8290.cd-rw2012-033 fatcat:rnkwgq4e3jd5rkhjo4fd7dgjmq