Effects of 5‐Fluorouracil on Mouse Bone Marrow

Radley, J.M.; Scurfield, G.

doi:10.1111/j.1365-2141.1979.tb03761.x

Cited by 51 publications

(29 citation statements)

References 32 publications

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“…Furthermore, expansion of Mk during platelet recovery was not accompanied by changes in ECM components distribution and contents. In contrast, the experiments demonstrated that on day 10 post-5-FU administration, Mks occupied most of the extravascular space within BM, with other myeloid cells almost absent [42]. These events were accompanied by an increase in BM content of ECM components and followed by peripheral platelets count recovery simultaneous with the regeneration of BM vasculature as described by Kopp et al [43].…”

Section: Discussionmentioning

confidence: 80%

Megakaryocytes Contribute to the Bone Marrow-Matrix Environment by Expressing Fibronectin, Type IV Collagen, and Laminin

et al. 2014

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Megakaryocytes associate with the bone marrow vasculature where they convert their cytoplasm into proplatelets that protrude through the vascular endothelium into the lumen and release platelets. The extracellular matrix (ECM) microenvironment plays a critical role in regulating these processes. In this work we demonstrate that, among bone marrow ECM components, fibronectin, type IV collagen and laminin are the most abundant around bone marrow sinusoids and constitute a peri-cellular matrix surrounding megakaryocytes. Most importantly, we report, for the first time, that megakaryocytes express components of the basement membrane and that these molecules contribute to the regulation of megakaryocyte development and bone marrow ECM homeostasis both in vitro and in vivo. In vitro, fibronectin induced a three-fold increase in the proliferation rate of mouse hematopoietic stem cells leading to higher megakaryocyte output with respect to cells treated only with thrombopoietin or other matrices. However, megakaryocyte ploidy level in fibronectin-treated cultures was significantly reduced. Stimulation with type IV collagen resulted in a 1.4-fold increase in megakaryocyte output, while all tested matrices supported proplatelet formation to a similar extent in megakaryocytes derived from fetal liver progenitor cells. In vivo, megakaryocyte expression of fibronectin and basement membrane components was up-regulated during bone marrow reconstitution upon 5-fluorouracil induced myelosuppression, while only type IV collagen resulted up-regulated upon induced thrombocytopenia. In conclusion, this work demonstrates that ECM components impact megakaryocyte behavior differently during their differentiation and highlights a new role for megakaryocyte as ECM-producing cells for the establishment of cell niches during bone marrow regeneration.

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Section: Discussionmentioning

confidence: 80%

Megakaryocytes Contribute to the Bone Marrow-Matrix Environment by Expressing Fibronectin, Type IV Collagen, and Laminin

et al. 2014

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“…Utilizing the well‐described hematopoietic recovery following 5‐FU injection [17, 18], we previously demonstrated that nine days following 150 mg/kg 5‐FU, platelets and femoral CFU‐Meg in rhG‐CSF‐treated splenectomized B 6 D 2 F 1 mice were significantly lower than in non‐rhG‐CSF‐treated controls, indicating an inhibitory influence of rhG‐CSF on megakaryocytopoietic recovery [16]. Interestingly, the beneficial effect of eight days of continuous rhG‐CSF on granulopoiesis resulting in an accelerated recovery of blood granulocytes was not observed when rhG‐CSF administration was delayed for five days.…”

Section: Discussionmentioning

confidence: 99%

Influence of rhG‐CSF Scheduling on Megakaryocytopoietic Recovery following 5‐Fluorouracil‐Induced Hematotoxicity in Splenectomized B ₆ D ₂ F ₁ Mice

1998

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Recombinant human granulocyte colony-stimulating factor, rhG-CSF, is widely applied to ameliorate neutropenia following chemotherapy. However, rhG-CSF can exert negative effects on megakaryocytopoiesis that might cause a delay of megakaryocyte recovery. Therefore, the present study was designed to test different rhG-CSF administration protocols with regard to their megakaryocytic inhibitory potential in a 5-fluorouracil (5-FU)-induced experimental model system. Splenectomized B 6 D 2 F 1 mice received a single injection of 5-FU (150 mg/kg) on day 0 followed by 50 µg/kg/day rhG-CSF given daily for either zero, four, or eight days. Five days after 5-FU, bone marrow and blood hematopoiesis were reduced significantly when compared with controls, independent of whether or not animals received rhG-CSF. However, nine days after 5-FU, granulopoietic recovery from 5-FU-induced toxicity was faster for rhG-CSF-treated versus untreated mice as demonstrated by higher values for colony forming unit-granulocyte macrophage (CFU-GM) and granulocytes (CFU-GM: 7.2 ± 0.4 versus 5 ± 0.6 × 10 4 /femur, granulocytes: 4.3 ± 2 versus 1.4 ± 0.4 × 10 5 /ml, respectively). Furthermore, significant mobilization of CFU-megakaryocyte (CFU-Meg) and CFU-GM into the peripheral blood was induced by the eight-day administration of rhG-CSF following 5-FU (day 9: 911 ± 102 CFU-Meg/ml, 2330 ± 152 CFU-GM/ml). However, megakaryocytic cells in these same mice were considerably lower when compared with those of animals receiving no rhG-CSF (CFU-Meg: 2.7 ± 0.2 × 10 3 versus 4.2 ± 0.2 × 10 3 /femur; small acetylcholinesterase positive (SAChE + ) cells: 4.9 ± 0.3 × 10 3 versus 7.3 ± 0.9 × 10 3 /femur; megakaryocytes: 2.5 ± 0.2 × 10 3 versus 4.1 ± 0.7 × 10 3 /femur; platelets: 2.67 ± 0.5 × 10 9 versus 3.1 ± 0.5 × 10 9 /ml, respectively). On the other hand, the shortening of the rhG-CSF treatment from eight to four days caused a rapid granulopoietic recovery comparable to animals receiving eight days of G-CSF with no significant delay in megakaryocytic recovery when compared with mice treated with 5-FU alone; however, with four days of rhG-CSF, the mobilization of CFU into the peripheral blood was significantly less effective. Taken together, the results showed that a shortening of rhG-CSF treatment after chemotherapy is capable of ameliorating neutropenia without negatively affecting megakaryocytopoietic recovery. If, however, maximum recruitment of CFU into the peripheral blood circulation by rhG-CSF for subsequent harvest and transplantation is needed, any shortening of rhG-CSF administration is not advisable.

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“…37 Hematopoietic recovery from 5-FU is dependent, in part, on the regenerating properties of quiescent HSCs that are induced to divide and differentiate in the immediate aftermath of 5-FU treatment. 38 Although progenitor or other non-HSC defects can also result in increased sensitivity to 5-FU, defects in HSC representation or function have been associated with increased 5-FU sensitivity in some contexts.…”

Section: Impaired Survival Of Mll5 ؊/؊ Mice Injected With 5-fumentioning

confidence: 99%

Mll5 contributes to hematopoietic stem cell fitness and homeostasis

Zhang¹,

Wong

Klinger³

et al. 2009

Blood

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IntroductionCytogenetic abnormalities that arise frequently in cancer cells are starting points for identifying genes that initiate or cooperate in tumorigenesis. In the study of leukemia in particular, major advances have come from the cloning of genes located at translocation breakpoints. Most notably, these genes have included BCR, ABL, MLL, PML, RARA, AML1/ RUNX1, and CBF␤, 1 many of which have proven to be essential for normal hematopoiesis in addition to their involvement in cancer.Segmental deletions, such as those involving chromosome bands 5q31, 7q22, and 20q12, are also recurring leukemiaassociated genomic abnormalities. In contrast to translocations, however, much less is known about how the deletions influence tumorigenesis. It is hypothesized that the deleted intervals contain tumor suppressor genes (TSGs) and that the deletion of these genes deregulates cell division, survival, or differentiation. It is unclear, however, whether such deregulation occurs solely as a consequence of haploinsufficiency of the putative TSGs 2,3 or whether "second-hit" mutations that result in biallelic inactivation are required.Loss of chromosome 7 (monosomy 7) and deletion of a segment of the long arm [del(7q)] are recurring cytogenetic abnormalities in myeloid malignancies, including myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), therapy-associated leukemia, and leukemias that arises in the context of inherited predispositions such as Fanconi anemia or neurofibromatosis type 1. 4 Many of these myeloid malignancies are associated with resistance to current treatments and a poor prognosis. Cytogenetic analysis of patients with myeloid disorders characterized by a del(7q) has revealed frequent involvement of band q22, and fluorescence in situ hybridization (FISH) studies of cases with proximal or distal breakpoints within 7q22 defined a commonly deleted segment (CDS) spanning 2.5 Mb that is bounded by D7S1503 and D7S1841 5 .Molecular analysis of the 14 known genes within this interval has not uncovered either pathogenic mutations or epigenetic silencing. 6,7 Here, we focus on the function of the mouse homolog of MLL5, a candidate TSG that is located within the 7q22 CDS. 8 MLL5 is a member of the mammalian Trithorax Group (trxG) of genes, several of which have been implicated in cancer. Most notably, MLL is a frequent target of translocations in leukemia, with more than 40 different fusion partner genes described to date. 9 Inactivation of the mouse homologue of MLL blocks definitive hematopoiesis in mouse embryos 10,11 and compromises hematopoietic stem cell (HSC) function. 12,13 Little is known about the normal function of MLL5. The gene is active in multiple tissues, with prominent expression in the hematopoietic system. 8,14 Overexpression or small interfering RNA-mediated knockdown of MLL5 causes cell-cycle arrest in multiple cell lines, 15,16 and an MLL5-GFP fusion protein localizes to foci in the nuclei of transfected cells. 15 Consistent with a possible role in cell-cycle regulation, Mll5 was r...

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Effects of 5‐Fluorouracil on Mouse Bone Marrow

Cited by 51 publications

References 32 publications

Megakaryocytes Contribute to the Bone Marrow-Matrix Environment by Expressing Fibronectin, Type IV Collagen, and Laminin

Megakaryocytes Contribute to the Bone Marrow-Matrix Environment by Expressing Fibronectin, Type IV Collagen, and Laminin

Influence of rhG‐CSF Scheduling on Megakaryocytopoietic Recovery following 5‐Fluorouracil‐Induced Hematotoxicity in Splenectomized B ₆ D ₂ F ₁ Mice

Mll5 contributes to hematopoietic stem cell fitness and homeostasis

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Effects of 5‐Fluorouracil on Mouse Bone Marrow

Cited by 51 publications

References 32 publications

Megakaryocytes Contribute to the Bone Marrow-Matrix Environment by Expressing Fibronectin, Type IV Collagen, and Laminin

Megakaryocytes Contribute to the Bone Marrow-Matrix Environment by Expressing Fibronectin, Type IV Collagen, and Laminin

Influence of rhG‐CSF Scheduling on Megakaryocytopoietic Recovery following 5‐Fluorouracil‐Induced Hematotoxicity in Splenectomized B 6 D 2 F 1 Mice

Mll5 contributes to hematopoietic stem cell fitness and homeostasis

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Product

Resources

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Influence of rhG‐CSF Scheduling on Megakaryocytopoietic Recovery following 5‐Fluorouracil‐Induced Hematotoxicity in Splenectomized B ₆ D ₂ F ₁ Mice