The critical role of DNA damage-inducible transcript 4 (DDIT4) in stemness character of leukemia cells and leukemia initiation.

Leukemia stem cells (LSCs) are critical for leukemia initiation, and the stemness properties of LSCs are related to disease relapse. Stemness properties, including quiescence, self-renewal, and chemoresistance, are maintained through an interplay between leukemia cells and the bone marrow (BM) niche. Here, we demonstrated that DNA damage-inducible transcript 4 (DDIT4) can be induced in a hypoxic BM niche and is required for the quiescence and self-renewal of AML1-ETO9a (AE9a)-transformed leukemia cells in vitro. More importantly, analysis of publicly available transcriptional data from adult acute myeloid leukemia (AML) patients revealed that elevated DDIT4 expression correlates with poor prognosis. Furthermore, DDIT4 knockout markedly suppressed leukemia initiation, quiescence, chemoresistance, and self-renewal of AE9a-transformed leukemia cells in vivo. Mechanistically, DDIT4 upregulates the expression of HOXA gene cluster, and re-expression of HOXA6 in DDIT4 knockout AE9a cells can rescue the impaired leukemia initiation. Our findings demonstrate the critical role of DDIT4 in the stemness of AE9a leukemia cells and elucidate its underlying mechanism, suggesting that targeting DDIT4 may represent a promising therapeutic strategy for eliminating LSCs in AML1-ETO leukemia.