Inhibition Of Bmp-Smad Pathway Reduces Leukemic Stemness In Pediatric Aml

Despite aggressive chemotherapy, relapse occurs in almost half of children with acute myeloid leukemia (AML), with very dismal survival. Novel and mechanism-driven therapies are desperately needed to conquer chemotherapy resistance and leukemic stemness in pediatric AML. Within the bone marrow niche, stromal cells protect leukemia cells from chemotherapy, maintain leukemic stemness, and eventually lead to disease recurrence. We developed an in vitro AML cell-stromal cell co-culture model to mimic bone marrow microenvironment. Stroma-leukemia cell interaction leads to activation of various signaling molecules in AML cells that allow them to evade apoptosis. One such example is extracellular signal-regulated kinases 1/2 (ERK1/2), important pro-survival proteins. ERK1/2 are activated by the Ras/Raf/ mitogen-activated protein kinase kinase (MAPK/ERK kinase or MEK) pathway downstream of signals from the stroma. We recently showed that stromal co-culture activates ERK1/2 in pediatric AML samples, contributing to chemotherapy resistance (Long, et al, 2017, Oncotarget, 8:90037).