HIF-1a activation is sufficient for the development of MDS

Hypoxia inducible factor-1a (HIF-1a) is a critical transcription factor for the hypoxic response, angiogenesis, normal hematopoietic stem cell regulation, and cancer development. Importantly, HIF-1a is also a key regulator for immune cell activation. In order to determine whether HIF-1a is sufficient for developing MDS phenotypes, we generated blood specific inducible HIF-1a transgenic mice. Using Vav1-Cre/Rosa26-loxP-Stop-loxP (LSL) rtTA driver, stable HIF-1a can be induced in a doxycycline administration dependent manner. After induction, HIF-1a-induced mice developed thrombocytopenia, leukocytopenia, macrocytic anemia, and multi-lineage dysplasia. We also found activation of both innate and adaptive immunity in HIF-1a- induced mice compared to those from control mice. Taken together, these data suggest that HIF-1a is sufficient to trigger a variety of key MDS features Overall design: Expression profiles of mRNA in HSPCs from constitutively active form of HIF1a protein induced mice and their control mice.

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Hayashi Y, Zhang Y, Yokota A, Yan X, Liu J, Choi K, Li B, Sashida G, Peng Y, Xu Z, Huang R, Zhang L, Freudiger GM, Wang J, Dong Y, Zhou Y, Wang J, Wu L, Bu J, Chen A, Zhao X, Sun X, Chetal K, Olsson A, Watanabe M, Romick-Rosendale LE, Harada H, Shih LY, Tse W, Bridges JP, Caligiuri MA, Huang T, Zheng Y, Witte DP, Wang QF, Qu CK, Salomonis N, Grimes HL, Nimer SD, Xiao Z, Huang G