Summary
After 35 years of research, the physiological regulator of platelet production has
been isolated and its gene cloned. This discovery originates from studies performed
with the myeloproliferative leukaemia virus (MPLV), a murine retrovirus which induces
an acute myeloproliferative syndrome in adult mice. MPLV carries the v-mpl oncogene
in its genome. This oncogene corresponds to a truncated form of the c-mpl proto-oncogene.
c-mpl encodes a cytokine receptor (Mpl-R) belonging to the hematopoietin receptor
superfamily. Among the hematopoietic cell lineages, Mpl-R is preferentially expressed
on late MK progenitors, megakaryocytes and platelets. The ligand for Mpl-R, called
Mpl-L, thrombopoietin (TPO), megakaryocyte growth and development factor (MGDF) or
megapoietin, is a gly-cosylated hormone of 322 amino acids in man which comprises
two domains; the N-terminus domain shares 50% similarity with erythropoietin and is
respon-sible for the biological activity; the C-terminus part is required for secretion.
In vitro Mpl-L is capable of directly inducing both the proliferation of MK progenitors
and the terminal maturation of megakaryocytes. MK grown in vitro in presence of Mpl-L
can shed platelets. Notwithstanding its major action on megakaryocytopoiesis and thrombocytopoiesis,
Mpl-L also potentiates the action of other cytokines on early hematopoietic progenitors.
The plasma level of Mpl-L inversely correlates with the platelet and MK mass. However,
in the two major organs (liver and kidney) which synthesize Mpl-L, there is no regulation
at the transcription level of the synthesis of Mpl-L by the platelet demand, suggesting
that regulation of the plasma level occurs by uptake and consumption at the level
of platelets. A deregulation of Mpl-L synthesis obtained by infecting, murine hematopoietic
stem cells by a retrovirus containing the coding sequence for Mpl-L induces a disease
which has many common features with idiopathic myelofibrosis in man. Therefore, Mpl-L
might be a very useful therapeutical cytokine to treat thrombocytopenia, but these
data emphasize that chronic exposure to Mpl-L may lead to a severe disease. Thus,
human clinical trials will require well controlled administration protocols.
Keywords
Megakaryocytopoiesis - platelet production - Mpl-receptor - Mpl-ligand - thrombopoietin
