Unconventional rapid ERK1,2 activation is indispensable for proliferation of the growth factor-independent myeloid leukemic cell line KG1

Abstract

While normal hematopoietic progenitor cells are dependent on colony-stimulating factors for in vitro proliferation, myeloid leukemic cells are frequently factor-independent. In this study we investigated several signalling intermediates of the Ras-Erk1,2 pathway which may be involved in the development of growth factor independence. In the growth factor independent cell line KG1, an extremely short activation pattern of Erk1,2 with a maximum at 30 s was observed in response to FBS. In contrast, stimulation of the IL-3 receptor in AML193 cells resulted in a transient Erk activation peaking at 5 min and returning to base levels after 15 min. Although the Erk activation in KG1 cells is short-lived, using the MEK inhibitor PD98059, we demonstrated that Erk phosphorylation is essential for proliferation of these cell lines. We also detected major differences in Shc phosphorylation between factor-dependent and -independent cells. These data suggest that Erk activation is essential for proliferation of growth factor-dependent and -independent leukemic cells. The minimal Erk activation observed in KG1 cells in response to serum is sufficient for mitogenesis of these cells.

Myeloid Leukemia Cell Growth and Differentiation Are Independent of Mitogen-activated Protein Kinase ERK1/2 Activation

“…PD98059 has been show to block the proliferation of different cancer cell lines (47)(48)(49) and can also prevent growth of the acute promyelocytic leukemia cell line KG1 (50). However, we found that PD98059 had no significant effects on the proliferation of most of the leukemic cell lines used in this study.…”

“…Nevertheless, this and other studies (32,46,50) show that variable degrees of ERK activity can be present in leukemias. Whether ERK activation could determine the susceptibility to different therapies or serve as a prognosis marker in myeloid leukemia merits some attention.…”

Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome

“…Figure 2A) (ERK is not constitutively phosphorylated in KG1A and is not, therefore, not examined here). 18 Cleaved caspase 3 and cleaved PARP increased with increasing inhibitor concentration indicating increased levels of apoptosis ( Figure 2B). These results are consistent with a recent study demonstrating activity of ponatinib against CUX1-FGFR1 transformed Ba/F3 cells.…”

Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer’s Disease

“…Aβ treatment can activate the MAPK signaling cascade in acute hippocampal slices as well as primary neurons (Ekinci et al 1999; Rapoport and Ferreira, 2000; Dineley et al 2001). ERK activation is a rapid, transient event with peak activation occurring within 2–5 min and returning to baseline after 15 min (Dabrowski et al 1997; Barge et al 1998; Porras et al 1998), and activity exceeding 1 h after exposure to a stimuli is indicative of sustained kinase activation (Dabrowski et al 1997). Our studies on primary neurons treated with oligomeric Aβ for as little as 5 min to as long as 24 h (only data from 24 h is shown) showed a significant increase in expression of Ras and phosphorylation of ERK only after 6 h of treatment, suggesting that chronic neuronal Aβ exposure elicits sustained MAPK signaling.…”