Loss of autophagy leads to failure in megakaryopoiesis, megakaryocyte differentiation, and thrombopoiesis in mice

Cao, Yan; Cai, Jinyang; Zhang, Suping; Yuan, Na; Li, Xin; Fang, Yixuan; Lin, Shiu‐Ru; Shang, Menglin; Liu, Shengbing; Zhao, Wei‐Li; Hu, Shaoyan; Wang, Jianrong

doi:10.1016/j.exphem.2015.01.001

Cited by 62 publications

(48 citation statements)

References 31 publications

(30 reference statements)

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“…Deletion of essential autophagy genes Atg7 or Fip200 in mouse HSCs leads to defective self-renewal and dysregulated myeloproliferation (15,17). In addition, recent studies of ours have shown that ATG7-dependent autophagy regulates cell cycles of HSCs and progenitor cells (18), promotes megakaryopoiesis, megakaryocyte differentiation, and thrombopoiesis (19), and regulates hematopoiesis largely via direct targeting Notch (20).…”

Section: Hematopoietic Stem Cells (Hsc)mentioning

confidence: 93%

Hierarchal Autophagic Divergence of Hematopoietic System

Cao

Zhang

Yuan

et al. 2015

Journal of Biological Chemistry

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Background: Autophagy is required in hematopoiesis and protects against leukemogenesis. Results: When ATG7-dependent canonical autophagy is impaired, ATG7-independent alternative autophagy engages in myeloid cells but not in hematopoietic stem cells. Conclusion:The integrity of hematopoietic stem cells is jeopardized by a lack of alternative autophagy. Significance: Learning autophagy organization in hematopoietic system is crucial for understanding hematopoietic stem cell transformation.

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Section: Hematopoietic Stem Cells (Hsc)mentioning

confidence: 93%

Hierarchal Autophagic Divergence of Hematopoietic System

Cao

Zhang

Yuan

et al. 2015

Journal of Biological Chemistry

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“…34,35 Autophagosome-like structures were noted in 3% of platelets from one affected member. Autophagy is known to be important in both megakary-opoiesis 36 and platelet function. 37 This observation thus suggests that autophagy may play a role in the pathophysiology of FLI1 -associated thrombocytopenia.…”

Section: Discussionmentioning

confidence: 99%

Macrothrombocytopenia and dense granule deficiency associated with FLI1 variants: ultrastructural and pathogenic features

et al. 2017

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Congenital macrothrombocytopenia is a family of rare diseases, of which a significant fraction remains to be genetically characterized. To analyze cases of unexplained thrombocytopenia, 27 individuals from a patient cohort of the Bleeding and Thrombosis Exploration Center of the University Hospital of Marseille were recruited for a high-throughput gene sequencing study. This strategy led to the identification of two novel FLI1 variants (c.1010G>A and c.1033A>G) responsible for macrothrombocytopenia. The FLI1 variant carriers’ platelets exhibited a defect in aggregation induced by low-dose adenosine diphosphate (ADP), collagen and thrombin receptor-activating peptide (TRAP), a defect in adenosine triphosphate (ATP) secretion, a reduced mepacrine uptake and release and a reduced CD63 expression upon TRAP stimulation. Precise ultrastructural analysis of platelet content was performed using transmission electron microscopy and focused ion beam scanning electron microscopy. Remarkably, dense granules were nearly absent in the carriers’ platelets, presumably due to a biogenesis defect. Additionally, 25–29% of the platelets displayed giant α-granules, while a smaller proportion displayed vacuoles (7–9%) and autophagosome-like structures (0–3%). In vitro study of megakaryocytes derived from circulating CD34+ cells of the carriers revealed a maturation defect and reduced proplatelet formation potential. The study of the FLI1 variants revealed a significant reduction in protein nuclear accumulation and transcriptional activity properties. Intraplatelet flow cytometry efficiently detected the biomarker MYH10 in FLI1 variant carriers. Overall, this study provides new insights into the phenotype, pathophysiology and diagnosis of FLI1 variant-associated thrombocytopenia.

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“…The physiological importance of Atg7 in autophagy was well characterized in several studies where Atg7 hematopoietic conditional knockout mice exhibited loss of autophagy and consequently induced cell death (6), whereas cardiac-specific inducible Atg7 transgenic mice displayed upregulated levels of autophagy and conferred protection against cardiac proteinopathy without an exhibition of Beclin-1 elevation (3). Similarly, our results show that AEE upregulates Atg7, which parallels with autophagy augmentation.…”

Section: Discussionmentioning

confidence: 99%