ID2 suppresses multiple myeloma cell proliferation by repressing the activity of the transcription factor TCF3

Abstract Transcription factors and their cofactors are major and selective non-oncogene dependencies in multiple myeloma (MM) cells. By performing a gain-of-function perturbation screen in human MM cell lines, we identified the ID genes as putative suppressors of MM cell fitness. Among them, ID2 was found to be downregulated in MM patient cells and acted as a tumor suppressor by directly binding and repressing the basic helix loop helix factor TCF3, also known as E2A. Lower ID2 expression in MM cells conferred a proliferative advantage by increasing TCF3 activity, leading to a dependency on this transcription factor. In contrast, ID2 overexpression reduced TCF3 binding to DNA, which resulted in cell-cycle arrest and a halt in MM cell proliferation. The myeloma bone marrow milieu supported this process by further decreasing the expression of ID2 and enhancing TCF3 activity, partly via IL-6, revealing a mechanism by which the tumor microenvironment impacts MM cell behavior.