Abstract
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 anti-apoptotic 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.
| Original language | English |
|---|---|
| Pages (from-to) | 4767-4773 |
| Number of pages | 7 |
| Journal | Cancer Research |
| Volume | 67 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - May 15 2007 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Chemotherapy-induced thrombocytopenia derives from the selective death of megakaryocyte progenitors and can be rescued by stem cell factor. / Zeuner, Ann; Signore, Michele; Martinetti, Daniela; Bartucci, Monica; Peschle, Cesare; De Maria, Ruggero.
In: Cancer Research, Vol. 67, No. 10, 15.05.2007, p. 4767-4773.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Chemotherapy-induced thrombocytopenia derives from the selective death of megakaryocyte progenitors and can be rescued by stem cell factor
AU - Zeuner, Ann
AU - Signore, Michele
AU - Martinetti, Daniela
AU - Bartucci, Monica
AU - Peschle, Cesare
AU - De Maria, Ruggero
PY - 2007/5/15
Y1 - 2007/5/15
N2 - 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 anti-apoptotic 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.
AB - 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 anti-apoptotic 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.
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U2 - 10.1158/0008-5472.CAN-06-4303
DO - 10.1158/0008-5472.CAN-06-4303
M3 - Article
VL - 67
SP - 4767
EP - 4773
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 10
ER -