<i>In vivo</i> effects of imatinib mesylate on human haematopoietic progenitor cells

Agis, Hermine; Jaeger, Eva; Doninger, Bianca; Sillaber, Christian; Marosi, Christine; Drach, Johannes; Schwarzinger, Ilse; Valent, Peter; Oehler, Leopold

doi:10.1111/j.1365-2362.2006.01645.x

Cited by 21 publications

(15 citation statements)

References 29 publications

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“…In vivo and in vitro evidence suggests that imatinib mesylate may directly inhibit normal hematopoiesis. 39,40 In our present study, we found that inhibition of PDGFR by imatinib mesylate inactivates PI3-k/Akt signaling and PDGF-induced anti-apoptosis in megakaryocytes. This suggests that blockade of PDGFR by imatinib mesylate may reduce megakaryocytopoiesis leading to thrombocytopenia, highlighting a crucial role for PDGF receptors in megakaryocytopoiesis.…”

Section: Discussionsupporting

confidence: 58%

Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway

Ye¹,

Chan²,

Qiao³

et al. 2010

Haematologica

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BackgroundPlatelet-derived growth factor is involved in the regulation of hematopoiesis. Imatinib mesylate, a platelet-derived growth factor receptor inhibitor, induces thrombocytopenia in a significant proportion of patients with chronic myeloid leukemia. Although our previous studies showed that platelet-derived growth factor enhances megakaryocytopoiesis in vitro, the in vivo effect of platelet-derived growth factor in a model of radiation-induced thrombocytopenia has not been reported. Design and MethodsIn this study, we investigated the effect of platelet-derived growth factor on hematopoietic stem/progenitor cells and platelet production using an irradiated-mouse model. We also explored the potential molecular mechanisms of platelet-derived growth factor on thrombopoiesis in M-07e cells. ResultsPlatelet-derived growth factor, like thrombopoietin, significantly promoted the recovery of platelets and the formation of bone marrow colony-forming unit-megakaryocyte in irradiated mice. Histology confirmed the protective effect of platelet-derived growth factor, as shown by an increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis. In a megakaryocytic apoptotic model, platelet-derived growth factor had a similar anti-apoptotic effect as thrombopoietin on megakaryocytes. We also demonstrated that platelet-derived growth factor activated the PI3-k/Akt signaling pathway, while addition of imatinib mesylate reduced p-Akt expression. ConclusionsOur findings show that platelet-derived growth factor enhances platelet recovery in mice with radiation-induced thrombocytopenia. This radioprotective effect is likely to be mediated via platelet-derived growth factor receptors with subsequent activation of the PI3-k/Akt pathway. We also provide a possible explanation that blockage of platelet-derived growth factor receptors may reduce thrombopoiesis and play a role in imatinib mesylate-induced thrombocytopenia.Key words: platelet-derived growth factor, thrombopoiesis, imatinib mesylate, thrombocytopenia, apoptosis. PI3-k/Akt pathway. Haematologica 2010;95(10):1745-1753. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Citation: Ye JY, Chan GC, Qiao L, Lian Q, Meng FI, Luo Q, Khachigian LM, Ma M, Deng R, Chen JL, Chong BH, and Yang M, Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway

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Section: Discussionsupporting

confidence: 58%

Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway

Ye¹,

Chan²,

Qiao³

et al. 2010

Haematologica

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“…Cells were washed, and were then grown in a methylcellulose culture essentially as described. 31 In brief, cells were seeded in 35 mm culture plates (2-5¥10 5 per well in triplicates) at 37°C (5% CO2) in 0.8% methylcellulose with 30% FCS, 10% bovine serum albumin (Gibco, Carlsbad, CA, USA), alphathioglycerol, GM-CSF (10 ng/mL) (R&D Systems, Minneapolis, MN, USA), IL-3 (5 ng/mL) (R&D), and erythropoietin (2 U/mL) (Roche, Basel, Switzerland). After 14 days, the numbers of CFU-GM, BFU-E, and CFU-GEMM were counted under an inverted microscope (Olympus, Tokyo, Japan).…”

Section: Clonogenic Assay and Evaluation Of Long-term Growth Of Leukementioning

confidence: 99%

“…32 Drug interactions were determined by calculating combination index (CI) values using Calcusyn software (Calcusyn; Biosoft, Ferguson, MO, USA). 30,31 A CI of less than 1 indicates synergy, a CI of 1 indicates additive effects, and a CI of more than 1 is indicative of antagonistic effects.…”

Section: Statistical Analysesmentioning

confidence: 99%

CD34+/CD38- stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin

Herrmann¹,

Cerny-Reiterer²,

Gleixner³

et al. 2011

Haematologica

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BackgroundCD33 is a well-known stem cell target in acute myeloid leukemia. So far, however, little is known about expression of CD33 on leukemic stem cells in chronic leukemias. Design and MethodsWe analyzed expression of CD33 in leukemic progenitors in chronic myeloid leukemia by multi-color flow cytometry and quantitative polymerase chain reaction. In addition, the effects of a CD33-targeting drug, gemtuzumab/ozogamicin, were examined. ResultsAs assessed by flow cytometry, stem cell-enriched CD34 -cells (>98% purity) displayed higher levels of CD33 mRNA. In chronic phase patients, CD33 was found to be expressed invariably on most or all stem cells, whereas in accelerated or blast phase of the disease, the levels of CD33 on stem cells varied from donor to donor. The MDR1 antigen, supposedly involved in resistance against ozogamicin, was not detectable on leukemic CD34 + /CD38 -cells. Correspondingly, gemtuzumab/ozogamicin produced growth inhibition in leukemic progenitor cells in all patients tested. The effects of gemtuzumab/ozogamicin were dose-dependent, occurred at low concentrations, and were accompanied by apoptosis in suspension culture. Moreover, the drug was found to inhibit growth of leukemic cells in a colony assay and long-term culture-initiating cell assay. Finally, gemtuzumab/ozogamicin was found to synergize with nilotinib and bosutinib in inducing growth inhibition in leukemic cells. Conclusions

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“…it is well-known a suppressive role of imatinib on the normal progenitor marrow cells [12,13] which is capable to induce at treatment start (when normal marrow cells are reduced) an early "acute" hematologic toxicity, usually reversible with progressive elimination of Ph1 cells and re-expansion of normal progenitor cells; after prolonged treatment in responsive patients, when almost all marrow progenitor cells are normal, imatinib could maintain its suppressive effect in a chronic way, with a less significant but prolonged clinical effect of chronic anemia. 2. at least for cases of chronic anemia with features of iron deficiency, imatinib could interfere with iron absorption and/or metabolism, leading to a condition of oral iron resistance.…”

Section: Discussionmentioning

confidence: 99%

Incidence of persistent/late chronic anemia in newly diagnosed patients with chronic myeloid leukemia responsive to imatinib

Latagliata

Volpicelli²,

Breccia

et al. 2014

American J Hematol

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In patients with chronic myeloid leukemia (CML) responsive to imatinib, it is still unknown whether the longlasting treatment could induce the appearance of a persistent/late chronic anemia. To highlight this issue, we revised 128 patients with CML (M/F 64/64, median age at diagnosis 56.9 years, interquartile range 43.0-69.3) treated at our Institution with 1st line imatinib for at least 36 months and in stable complete cytogenetic response. At the 36th month of imatinib, a chronic anemia (Hb < 12 g/dl for > 6 months) was present in 38/128 patients (29.6%): the anemia was moderate (Hb > 8 10 g/dl) in 12 patients (9.3%) and mild (Hb > 10 < 12 g/dl) in 26 patients (20.3%). All patients with persistent/late chronic anemia had a low reticulocyte count and 8/38 a condition of iron deficiency without clinical and instrumental signs of chronic blood loss. Four out of 38 patients (10.5%) needed red cell transfusions during the follow-up. At a landmark analysis from the 36th month of imatinib treatment, cumulative 4-year overall survival (OS) for patients with chronic anemia was 94.4% (CI 95% 83.8-100) compared to 93.5% (CI 95% 87.2-99.8) for patients without chronic anemia (P 5 0.617). In conclusion, the occurrence of a late chronic anemia during long-lasting treatment with imatinib has been observed in about 30% of our responsive patients: its occurrence does not seem to affect OS, but its real impact should be evaluated on a larger cohort of patients. Am. J.

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In vivo effects of imatinib mesylate on human haematopoietic progenitor cells

Abstract: This study suggests that imatinib exerts myelosuppressive effects through inhibition of haematopoietic progenitor cells.

Cited by 21 publications

References 29 publications

Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway

Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway

CD34+/CD38- stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin

Incidence of persistent/late chronic anemia in newly diagnosed patients with chronic myeloid leukemia responsive to imatinib

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