EXPRESSION AND FUNCTION OF THE MEGAKARYOCYTE GROWTH AND DEVELOPMENT FACTOR-RECEPTOR IN ACUTE MYELOID-LEUKEMIA BLASTS

The receptor for megakaryocyte growth and development factor (MGDF), a lso known as thrombopoietin, has recently been cloned. MGDF stimulates platelet production and maturation both in vitro and in vivo. MGDF ma y thus have a role in attenuating the thrombocytopenia associated with acute myeloid leukemia (AML) and its therapy. However, there is conce rn that MGDF might induce AML blast proliferation and thereby increase the risk of treatment failure. To address this concern, we studied th e expression of c-mpl mRNA and c-Mpl protein by blasts from AML patien ts. In addition we examined the in vitro effect of MGDF as well as the combined effect of MGDF and granulocyte colony-stimulating factor (G- CSF) or stem cell factor (SCF) on leukemic blast proliferation, recrui tment into S-phase, induction of programmed cell death and activation of signal transducers and activators of transcription (STAT) proteins. Our results demonstrate that blasts from a substantial proportion of cases of AML express the receptor at either the mRNA or protein level. Moreover, the function of the MGDF receptor was demonstrated by activ ation of STAT proteins following exposure to MGDF. Nevertheless, blast proliferation in response to MGDF was rare, and the proliferative eff ect of MGDF was less than that of G-CSF or SCF. Furthermore, MGDF did not prevent programmed cell death induced by cytarabine. Finally, ther e appeared to be no correlation between receptor expression by AML bla sts and functional response to MGDF. Based on these data, it would app ear that clinical trials of MGDF may be undertaken safely in patients with AML.