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Blood, 15 October 2001, Vol. 98, No. 8, pp. 2372-2381
HEMATOPOIESIS
Alterations of the phosphoinositide 3-kinase and
mitogen-activated protein kinase signaling pathways in the
erythropoietin-independent Spi-1/PU.1 transgenic
proerythroblasts
Stéphane Barnache,
Patrick Mayeux,
Bernard Payrastre, and
Françoise Moreau-Gachelin
From Inserm U528, Institut Curie, Paris, France and
Inserm U363, Hôpital Cochin, Paris, France; and Inserm U326, CHU
Purpan, Toulouse, France.
During the cell transformation processes leading to
erythroleukemia, erythroid progenitors often become erythropoietin
(Epo)-independent for their proliferation. The biochemical events that
could lead an erythroleukemic cell to growth factor-independence were
investigated using spi-1 transgenic
poerythroblasts. Spi-1/PU.1 is a myeloid and B-cell transcription
factor of the ETS family and is activated by insertional
mutagenesis during Friend erythroleukemia. Its overexpression in
proerythroblasts induces their differentiation arrest without altering
their erythropoietin requirement for proliferation (HS1 cells). At a
later step, genetic alterations most probably occur allowing
spi-1 transgenic poerythroblasts to proliferate in the
absence of erythropoietin (HS2 cells). The signaling
transduction pathways in HS1 and HS2 proerythroblasts
were analyzed. The authors have previously shown that the
Jak/STAT pathway was not activated in Epo-independent cells,
but remained sensitive to Epo stimulation. In the present study, it is
shown that the Epo-independent proliferation of HS2 cells
requires active phosphoinositide 3-kinase (PI3K) and mitogen-activated
protein kinase (MAPK) pathways. In these cells, PI3K was constitutively
associated with the molecular adapters Grb2 and Gab1, and with the
phosphatases SHP-2 and SHIP. Moreover, PI3K activity was correlated
with the constitutive phosphorylation of serine-threonine protein
kinase (AKT) in HS2 cells. Lastly, a constitutive activation of
the MAPKs extracellular signal-regulated kinases (ERK1/2) in
HS2 cells was observed that occurs in a PI3K-independent manner, but depends strictly on the activity of the protein kinase C
(PKC). These results suggest that constitutive activations of PI3K/AKT and PKC/MAPK pathways can act in synergy to lead a
proerythroblast to proliferate without Epo.
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