Defective erythroid maturation in gelsolin mutant mice

Cantù, Claudio; Bosè, Francesca; Bianchi, Paola; Reali, Eva; Colzani, Maria; Cantù, Ileana; Barbarani, Gloria; Ottolenghi, Sergio; Witke, Walter; Spinardi, Laura

doi:10.3324/haematol.2011.052522

Cited by 9 publications

(10 citation statements)

References 32 publications

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“…Histological assessment of the gross structure of liver lobules did not indicate any obvious difference in morphology which would be indicative of SOS between the control group and 30 mg/kg dosage group at 'Day 23' and 'Day 30' or the 15 mg/kg dosage group at 'Day 30' (Fig 6A-6D). However, there were clusters of dark stained nucleated cells embedded throughout the liver tissue of the 30 mg/kg dosage group at 'Day 30' that were not present in any other treatment group (Fig 6D insert) and are characteristic of extramedullary haematopoiesis [22]. Observation of hepatocytes under high magnification also indicated less intracellular granular structures in oxaliplatin-treated mice (Fig 6E-6H).…”

Section: No Indication Of Sos In Chronic Oxaliplatin-treated Micementioning

confidence: 90%

Oxaliplatin-induced haematological toxicity and splenomegaly in mice

et al. 2020

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Haematological toxicities occur in patients receiving oxaliplatin. Mild anaemia (grade 1-2) is a common side effect and approximately 90% of recipients develop measurable spleen enlargement. Although generally asymptomatic, oxaliplatin-induced splenomegaly is independently associated with complications following liver resection for colorectal liver metastasis and separately with poorer patient outcomes. Here, we investigated oxaliplatin-induced haematological toxicities and splenomegaly in mice treated with escalating dosages comparable to those prescribed to colorectal cancer patients. Methods Blood was analysed, and smears assessed using Wright-Giemsa staining. Paw coloration was quantified as a marker of anaemia. Spleen weight and morphology were assessed for abnormalities relating to splenomegaly and a flow cytometry and multiplex cytokine array assessment was performed on splenocytes. The liver was assessed for sinusoidal obstructive syndrome.

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Section: No Indication Of Sos In Chronic Oxaliplatin-treated Micementioning

confidence: 90%

Oxaliplatin-induced haematological toxicity and splenomegaly in mice

et al. 2020

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“…Cdk6 directly regulates the transcription of Gelsolin and Baiap2 as we were able to further show enhanced binding of Cdk6 to the respective promoters by chromatin immunoprecipitation assays in the non-transformed mouse progenitor HPC7 cell line and in Bcr/Abl p185+ -transformed lymphoid cells ( Figure 6B ). Lymphoid cell expression of gelsolin, a known regulator of actin filament (de-)polymerization, 19 was also decreased in Cdk6 K43M/K43M mice ( Online Supplementary Figure S7B ).…”

Section: Resultsmentioning

confidence: 98%

“…Among those, gelsolin, a Ca ++ -dependent protein, severs pre-assembled actin filaments and is hence crucial in actin remodeling. 19 …”

Section: Introductionmentioning

confidence: 99%

Cdk6 contributes to cytoskeletal stability in erythroid cells

et al. 2017

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Mice lacking Cdk6 kinase activity suffer from mild anemia accompanied by elevated numbers of Ter119+ cells in the bone marrow. The animals show hardly any alterations in erythroid development, indicating that Cdk6 is not required for proliferation and maturation of erythroid cells. There is also no difference in stress erythropoiesis following hemolysis in vivo. However, Cdk6−/− erythrocytes have a shortened lifespan and are more sensitive to mechanical stress in vitro, suggesting differences in cytoskeletal architecture. Erythroblasts contain both Cdk4 and Cdk6, while mature erythrocytes apparently lack Cdk4 and their Cdk6 is partly associated with the cytoskeleton. We used mass spectrometry to show that Cdk6 interacts with a number of proteins involved in cytoskeleton organization. Cdk6−/− erythroblasts show impaired F-actin formation and lower levels of gelsolin, which interacts with Cdk6. We also found that Cdk6 regulates the transcription of a panel of genes involved in actin (de-)polymerization. Cdk6-deficient cells are sensitive to drugs that interfere with the cytoskeleton, suggesting that our findings are relevant to the treatment of patients with anemia – and may be relevant to cancer patients treated with the new generation of CDK6 inhibitors.

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“…Of note, calcium signaling may also coordinately regulate other proteins involved in the enucleation process. For example, gelsolin, a Ca 2+ -activated actin filament has been shown to be critical for terminal erythroid maturation and enucleation [ 25 ], suggesting that the transient calcium uptake/calcium flux may be required for extensive gelsolin-dependent actin remodeling required for the enucleation process ( Fig 5 ). Similarly, calcium is thought to regulate translocation and activation of Rac GTPases [ 26 ].…”

Section: Resultsmentioning

confidence: 99%

Calcium Signaling Is Required for Erythroid Enucleation

et al. 2016

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Although erythroid enucleation, the property of erythroblasts to expel their nucleus, has been known for 7ore than a century, surprisingly little is known regarding the molecular mechanisms governing this unique developmental process. Here we show that similar to cytokinesis, nuclear extrusion requires intracellular calcium signaling and signal transduction through the calmodulin (CaM) pathway. However, in contrast to cytokinesis we found that orthochromatic erythroblasts require uptake of extracellular calcium to enucleate. Together these functional studies highlight a critical role for calcium signaling in the regulation of erythroid enucleation.

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Defective erythroid maturation in gelsolin mutant mice

Cited by 9 publications

References 32 publications

Oxaliplatin-induced haematological toxicity and splenomegaly in mice

Oxaliplatin-induced haematological toxicity and splenomegaly in mice

Cdk6 contributes to cytoskeletal stability in erythroid cells

Calcium Signaling Is Required for Erythroid Enucleation

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