The cell non-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment.

The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSC) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which BMM maintains LSC may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSC previously identified by us, controls cytokine production in the BMM, but the role of ID1 in AML-BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of AML patients, especially in bone marrow mesenchymal stem cells (BMSCs), and the high expression of ID1 in AML-BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of co-cultured AML cells. Loss of Id1 in BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells co-cultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction by truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1 deficient bone marrow supernatant fluid (BMSF) to regulate AML progression in mice. Taken together, our study highlights the critical role of ID1 in AML-BMM and aids the development of therapeutic strategies for AML.