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), also known as thrombopoietin, has recently been cloned. MGDF stimulates platelet production and maturation both in vitro and in vivo. MGDF may thus have a role in attenuating the thrombocytopenia associated with acute myeloid leukemia (AML) and its therapy. However, there is concern that MGDF might induce AML blast proliferation and thereby increase the risk of treatment failure. To address this concern, we studied the expression of c-mpl mRNA and c-Mpl protein by blasts from AML patients. 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, recruitment 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 activation of STAT proteins following exposure to MGDF. Nevertheless, blast proliferation in response to MGDF was rare, and the proliferative effect of MGDF was less than that of G-CSF or SCF. Furthermore, MGDF did not prevent programmed cell death induced by cytarabine. Finally, there appeared to be no correlation between receptor expression by AML blasts and functional response to MGDF. Based on these data, it would appear that clinical trials of MGDF may be undertaken safely in patients with AML.
Wetzler
M
M
Department of Hematologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Bernstein
S H
SH
Baumann
H
H
Fries
K M
KM
Stewart
C
C
Blumenson
L
L
Baer
M R
MR
Herzig
G P
GP
Bloomfield
C D
CD
Slack
J L
JL
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D004347:Drug Interactions; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology; D013926:Thrombopoietin / Q000378:metabolism* / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D019089:Stem Cell Factor; D015534:Trans-Activators; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; C082218:MPL protein, human; D013926:Thrombopoietin; D013936:Thymidine