ID2 downregulation promotes tumor cell proliferation via elevated TCF3 activity in Multiple Myeloma [RNA-Seq]

Multiple myeloma (MM) is characterized by rewired transcriptional circuits. Transcription factors and their cofactors are major and selective non-oncogene dependencies in MM cells. By performing a gain-of-function (GOF) perturbation screen in MM cell lines, we identified the Inhibitor of DNA binding (ID) proteins as putative suppressors of MM cell fitness. Among the ID genes, ID2 was found to be downregulated in MM patient cells and acted as a tumor suppressor by directly binding and repressing the transcription factor TCF3. Lower ID2 expression in MM cells conferred a proliferative advantage by allowing higher TCF3 activity in tumor cells, resulting in a striking dependency on this TF. To the contrary, ID2 overexpression reduced TCF3 binding to DNA and rewired the MM transcriptome, leading to cell-cycle arrest and senescence. The myeloma bone marrow milieu participates in this process by further decreasing the expression of ID2 and enhancing TCF3 activity, revealing a novel mechanism by which the tumor microenvironment controls MM cell behavior.