NADPH oxidases regulate cell growth and migration in myeloid cells transformed by oncogenic tyrosine kinases.
Transformation by tyrosine kinase oncogenes (TKOs) in myeloid malignancies, including BCR-ABL in chronic myeloid leukemia, FLT3ITD in acute myeloid leukemia or JAK2V617F in myeloproliferative neoplasms, is associated with increased growth and cytoskeletal abnormalities. Using targeted approaches against components of the superoxide-producing NADPH-oxidases, including NADPH oxidase 2 (NOX2), NOX4 and the common p22(phox) subunit of NOX1-4, myeloid cells were found to display reduced cell growth and spontaneous migration. Consistent with a role of NOXs as regulators of membrane proximal signaling events in nonphagocytic cells, NOX2 and NOX4 were not involved in the excess production of intracellular reactive oxygen species and did not significantly increase oxygen consumption. All NOX family members are controlled in part through levels of the rate-limiting substrate NADPH, which was found to be significantly elevated in TKO-transformed cells. Also, reduced phosphorylation of the actin filament crosslinking protein myristoylated alanine-rich C-kinase substrate (MARCKS) in response to suppression of p22(phox) hints at a novel effector of NOX signaling. MARCKS was also found to be required for increased migration. Overall, these data suggest a model whereby NOX links metabolic NADPH production to cellular events that directly contribute to transformation.
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
M M
MM
Reddy
M S
MS
Fernandes
R
R
Salgia
R L
RL
Levine
J D
JD
Griffin
M
M
Sattler
D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000473:pathology*; D009249:NADP / Q000096:biosynthesis; D019255:NADPH Oxidases / Q000502:physiology*; D009857:Oncogenes; D011505:Protein-Tyrosine Kinases / Q000235:genetics*
D009249:NADP; D019255:NADPH Oxidases; D011505:Protein-Tyrosine Kinases