Deregulation of the CDX2-KLF4 axis in acute myeloid leukemia and colon cancer

Commentary on: CDX2-driven myeloid leukemogenesis involves KLF4 repression and deregulated PPAR gamma signaling Acute myeloid leukemia (AML), the most common acute leukemia in adults, is characterized by enormous genetic and biological heterogeneity. As a consequence, the identification of unifying pathogenetic mechanisms and common targets for therapy has been next to impossible. We and others previously showed that the non-clustered homeobox gene CDX2, which encodes a transcription factor involved in embryonic development and intestinal cell homeostasis, is aberrantly expressed in nearly all cases of AML and promotes leukemogenesis, whereas CDX2 expression is absent in normal hematopoietic stem and progenitor cells (HSPC) [1,2]. These findings had pointed to the potential of targeting CDX2 in AML; however, little was known about the effectors through which CDX2 contributes to AML development, and specific strategies for interfering with CDX2 function in patients had remained elusive. We recently addressed these unresolved issues [3]. Analysis of the transcriptional effects of Cdx2 in primary murine HSPC and a mouse model of Cdx2-driven leukemia, followed by intersection with data from genome-wide expression analysis of a large AML patient cohort identified the zinc-finger protein KLF4, an established tumor suppressor in certain epithelial and B-cell malignancies [4-6], as an essential CDX2 target. CDX2 silenced KLF4 transcription through binding to the KLF4 upstream regulatory region and a decrease in histone 3 lysine 4 trimethylation (H3K4me3) at the KLF4 promoter mediated by the H3K4 demethylase KDM5B. In support of a tumor-suppressive role for KLF4 in CDX2-driven AML, exogenous KLF4 induced cell cycle arrest, apoptosis, and differentiation preferentially in cultured myeloid leukemia cells that express CDX2. Furthermore, KLF4 inhibited the development of Cdx2-induced murine leukemias in competitive and non-competitive bone marrow transplantation experiments. A chemical genomic analysis based on the Connectivity Map [7] revealed that the transcriptional changes induced by CDX2 in hematopoietic cells were counteracted by drugs that stimulate the nuclear receptor PPARγ. Of potential clinical-translational relevance, PPARγ agonists also upregulated KLF4 and were toxic to CDX2-expressing myeloid leukemia cells, which were found to display altered PPARγ signaling both in vitro and in vivo, but not to normal HSPC. In addition to elucidating the role of CDX2 in leukemia, these findings also provided insight into the opposing effects of CDX2 in AML and colon cancer, where CDX2 can function as a tumor suppressor [8]. Specifically, we observed that in colonic epithelial cells, KLF4 is positively regulated by CDX2, and consistent with its tissue-specific …