RUNX1 Is a Tumor Suppressor in T-ALL

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 expression 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.

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