ELK1 promotes the progress of myeloid leukemia by hindering the differentiation of neutrophils

The genes controlling lineage determination and differentiation tend to be essential for the development of acute myeloid leukemia (AML). Identifying novel target genes capable of promoting the differentiation and maturation of undifferentiated leukemia cells offers a promising therapeutic strategy for the treatment of AML. We used conditional Elk1 and KrasG12D expression mice, along with Mx1-Cre, Lyz2-Cre and Elane-Cre drive strains (which enable stage specific control of Elk1 or KrasG12D expression), to investigate the function of Elk1 in the hematopoiesis and leukemogenesis. Bone marrow transplantation assay was performed to explore the function of Elk1 in hematopoiesis under stress conditions. Additionally, bulk-cell RNA sequencing, single-cell RNA sequencing and proteomics were performed to reveal the signaling pathways altered by Elk1. Finally, undifferentiated leukemia cells were used to verify whether inhibiting ELK1 could promote the differentiation of these cells into mature neutrophils. ELK1 is highly expressed in undifferentiated AML cells. Studies using mouse model demonstrated that overexpression of Elk1 accelerates the development of KrasG12D-induced myeloid leukemia by impairing the stemness of hematopoietic stem cells (HSCs) and impeding the differentiation of neutrophils. Furthermore, impeding the maturation of neutrophils independently promotes the development of KrasG12D mutation-induced myeloid leukemia. Meanwhile, our in vitro experiments preliminarily confirmed that inhibiting ELK1 suppresses the proliferation of leukemia cells and induces the differentiation of CD15 + CD66b - myeloid progenitor cells into CD15 + CD66b + neutrophils. Our study demonstrates that ELK1 is a potential therapeutic target for AML, due to its critical role in regulating neutrophils differentiation.