Caudal Type Homeobox 2 Is Required for Leukemogenesis but Not for Normal Hematopoieisis

Caudal Type Homeobox 2 (CDX2) is a caudal-related homeobox family transcription factor known to be developmental regulator involved in murine axial elongation and anteroposterior vertebral patterning and cell fate determination in the intestine. In adults, CDX2 expression is restricted to the small intestine and the colon. Interestingly, CDX2 is overexpressed in ~90% of human acute myeloid leukemias and the majority of acute lymphoblastic leukemias. Hence, aberrant expression of CDX2 may play a contributing role in leukemogenesis. The role of CDX2 in normal hematopoietic development is unknown. To assess the role of CDX2 in normal hematopoiesis we characterized hematopoietic development in Cdx2 fl/fl Mx1-Cre+ mice after poly (I:C)-mediated gene deletion compared to wildtype littermates. Under steady state conditions, no significant defects were identified in long-term hematopoietic stem cells (LT-HSCs), multipotent progenitors, myeloid progenitors, or mature cell lineages. To test if long-term hematopoietic stem cells were functionally impaired following Cdx2 deletion, competitive transplantation assays were performed. We found that CDX2 was not required for long-term hematopoietic reconstitution in the competitive transplant setting. Together, these data establish that CDX2 is not required for adult steady state hematopoiesis or LT-HSC function. We then asked whether or not CDX2 was essential for leukemogenesis. To interrogate this, Cdx2 fl/fl Mx1-Cre+, Cdx2 fl/+ Mx1-Cre+, and wildtype littermates were treated with poly (I:C) to facilitate gene deletion or for control purposes. Bone marrow cells from the mice were then transformed using well-established HOXA9/MEIS1 or MLL-AF10 leukemogenesis models. In both systems, Cdx2-deficiency prevented leukemia development, whereas wildtype controls succumbed to leukemia within 200 days. Cdx2 heterozygous knockout animals had a delayed onset of leukemia compared to wildtype animals. Taken together, these data indicate that CDX2 is not required for steady state adult hematopoiesis or LT-HSC function, but is necessary for the development of leukemia. Our findings suggest CDX2 has potential as a novel therapeutic target that could be exploited in the majority of AML and ALL patients across a broad mutational spectrum. The nomination of CDX2 as a key target for the majority of leukemias is significant, as current targeted treatment strategies are limited to only particular patient subsets.