Constitutively activated MAPK and AKT signaling pathways are often found in solid
tumors and
leukemias. PTEN is one of the
tumor suppressors that are frequently found deficient in patients with late-stage
cancers or
leukemias. In this study we demonstrate that a MAPK inhibitor,
PD98059, inhibits both AKT and ERK phosphorylation in a human
myeloid leukemia cell line (TF-1), but not in PTEN-deficient
leukemia cells (TF-1a). Ectopic expression of wild-type PTEN in
myeloid leukemia cells restored
cytokine responsiveness at physiological concentrations of
GM-CSF (<0.02 ng/mL) and significantly improved cell sensitivity to MAPK inhibitor. We also found that Early Growth Response 1 (EGR1) was constitutively over-expressed in
cytokine-independent TF-1a cells, and ectopic expression of PTEN down-regulated EGR1 expression and restored dynamics of EGR1 expression in response to
GM-CSF stimulation. Data from primary bone marrow cells from mice with Pten deletion further supports that PTEN is indispensible for
myeloid leukemia cells in response to MAPK inhibitors. Finally, We demonstrate that the absence of EGR1 expression dynamics in response to
GM-CSF stimulation is one of the mechanisms underlying drug resistance to MAPK inhibitors in
leukemia cells with PTEN deficiency. Our data suggest a novel mechanism of PTEN in regulating expression of EGR1 in hematopoietic cells in response to
cytokine stimulation. In conclusion, this study demonstrates that PTEN is dispensable for
myeloid leukemia cells in response to MAPK inhibitors, and PTEN regulates EGR1 expression and contributes to the
cytokine sensitivity in
leukemia cells.