B7-H4 enhances the differentiation of murine leukemia-initiating cells via the PTEN/AKT/RCOR2/RUNX1 pathways

Leukemia-initiating cells (LICs) are believed to be responsible for the initiation, development and relapse of leukemia.1 To effectively eliminate LICs, new molecular targets and therapeutic strategies for targeting either extracellular or intracellular signaling are needed. Studies from our and other groups have suggested that targeting specific surface immune molecules of LICs, including LILRB2,2 CD123,3 CD474 and CD93,5 may be a promising strategy to block leukemogenesis. To identify more such surface immune molecules, we screened approximately 30 cell surface proteins expressed in immune systems, and found that several immune molecules, including IREM-1, BTLA, CD244, JAM3, B7-H1 and B7-H4, were highly expressed on MLL-AF9-induced human acute myeloid leukemia (AML) cells.6 Interestingly, one of the identified candidates B7-H4 was also expressed on one fraction of human LIC-enriched CD34+ AML cells as determined by flow cytometric analysis (Supplementary Figure 1a). More importantly, in silico analysis using data extracted from the curated database Leukemia Gene Atlas (http://www.leukemia-gene-atlas.org) also showed that B7-H4 expression level was positively correlated with the overall survival of AML patients (Supplementary Figure 1b), indicating that B7-H4 may serve as a tumor suppressor during leukemia development.