Chemotherapy-induced thrombocytopenia derives from the selective death of megakaryocyte progenitors and can be rescued by stem cell factor.
Thrombocytopenia is a common side effect of chemotherapy, responsible for increased risk of bleeding and delay of treatment schedules in cancer patients. It is currently unknown how chemotherapeutic agents affect platelet production and whether the platelet precursors megakaryocytes represent a direct target of cytotoxic drugs. We investigated the effects of chemotherapeutic agents on primary megakaryocytes by using a culture system that recapitulates in vitro human megakaryopoiesis and found that cytotoxic drugs predominantly destroyed megakaryocytic progenitors at early stages of differentiation. Immature megakaryocytes could be protected from chemotherapeutic agents by the cytokine stem cell factor (SCF), which binds the c-kit receptor expressed on hematopoietic stem and progenitor cells. In chemotherapy-treated megakaryocytes, SCF activated Akt, neutralized the mitochondrial apoptotic machinery, and inhibited caspase activity. Interfering with Akt activation abrogated the antiapoptotic effects of SCF, whereas exogenous expression of constitutively active Akt inhibited drug-induced apoptosis of primary megakaryocytes, indicating the Akt pathway as primarily responsible for SCF-mediated protection of megakaryocyte progenitors. These results indicate apoptosis of megakaryocyte progenitors as a major cause of chemotherapy-induced thrombocytopenia and suggest that SCF may be used to prevent platelet loss in cancer patients with c-kit-negative tumors.
Zeuner
Ann
A
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy. a.zeuner@iss.it
Signore
Michele
M
Martinetti
Daniela
D
Bartucci
Monica
M
Peschle
Cesare
C
De Maria
Ruggero
R
D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology; D003561:Cytarabine / Q000009:adverse effects / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015672:Erythroid Precursor Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008533:Megakaryocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D019089:Stem Cell Factor / Q000494:pharmacology*; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced* / Q000473:pathology*; D014750:Vincristine / Q000009:adverse effects / Q000494:pharmacology
D000970:Antineoplastic Agents; D019089:Stem Cell Factor; D003561:Cytarabine; D014750:Vincristine; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin