Enhancing mitochondrial function in vivo rescues MDS-like anemia induced by pRb deficiency
(2020) In Experimental Hematology 88. p.28-41- Abstract
Erythropoiesis is intimately coupled to cell division, and deletion of the cell cycle regulator retinoblastoma protein (pRb) causes anemia in mice. Erythroid-specific deletion of pRb has been found to result in inefficient erythropoiesis because of deregulated coordination of cell cycle exit and mitochondrial biogenesis. However, the pathophysiology remains to be fully described, and further characterization of the link between cell cycle regulation and mitochondrial function is needed. To this end we further assessed conditional erythroid-specific deletion of pRb. This resulted in macrocytic anemia, despite elevated levels of erythropoietin (Epo), and an accumulation of erythroid progenitors in the bone marrow, a phenotype strongly... (More)
Erythropoiesis is intimately coupled to cell division, and deletion of the cell cycle regulator retinoblastoma protein (pRb) causes anemia in mice. Erythroid-specific deletion of pRb has been found to result in inefficient erythropoiesis because of deregulated coordination of cell cycle exit and mitochondrial biogenesis. However, the pathophysiology remains to be fully described, and further characterization of the link between cell cycle regulation and mitochondrial function is needed. To this end we further assessed conditional erythroid-specific deletion of pRb. This resulted in macrocytic anemia, despite elevated levels of erythropoietin (Epo), and an accumulation of erythroid progenitors in the bone marrow, a phenotype strongly resembling refractory anemia associated with myelodysplastic syndromes (MDS). Using high-fractionation fluorescence-activated cell sorting analysis for improved phenotypic characterization, we illustrate that erythroid differentiation was disrupted at the orthochromatic stage. Transcriptional profiling of sequential purified populations revealed failure to upregulate genes critical for mitochondrial function such as Pgc1β, Alas2, and Abcb7 specifically at the block, together with disturbed heme production and iron transport. Notably, deregulated ABCB7 causes ring sideroblastic anemia in MDS patients, and the mitochondrial co-activator PGC1β is heterozygously lost in del5q MDS. Importantly, the anemia could be rescued through enhanced PPAR signaling in vivo via either overexpression of Pgc1β or bezafibrate administration. In conclusion, lack of pRb results in MDS-like anemia with disrupted differentiation and impaired mitochondrial function at the orthochromatic erythroblast stage. Our findings reveal for the first time a role for pRb in heme and iron regulation, and indicate that pRb-induced anemia can be rescued in vivo through therapeutic enhancement of PPAR signaling.
(Less)
- author
- Sen, Taha LU ; Jain, Mayur LU ; Gram, Magnus LU ; Mattebo, Alexander LU ; Soneji, Shamit LU ; Walkley, Carl R. and Singbrant, Sofie LU
- organization
-
- Stem cell and red cell biology (research group)
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Stem Cell Center
- Hematopoiesis and Gene Therapy (research group)
- Antioxidation medicine (research group)
- LUCC: Lund University Cancer Centre
- Stem Cells to Red Blood Cells (research group)
- Division of Molecular Hematology (DMH)
- publishing date
- 2020-08-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Experimental Hematology
- volume
- 88
- pages
- 14 pages
- publisher
- Elsevier
- external identifiers
-
- pmid:32629063
- scopus:85088937710
- ISSN
- 0301-472X
- DOI
- 10.1016/j.exphem.2020.06.006
- language
- English
- LU publication?
- yes
- id
- 31bac181-567f-4fb1-8f37-ab896e227d8f
- date added to LUP
- 2020-08-13 13:05:17
- date last changed
- 2024-08-22 02:38:15
@article{31bac181-567f-4fb1-8f37-ab896e227d8f, abstract = {{<p>Erythropoiesis is intimately coupled to cell division, and deletion of the cell cycle regulator retinoblastoma protein (pRb) causes anemia in mice. Erythroid-specific deletion of pRb has been found to result in inefficient erythropoiesis because of deregulated coordination of cell cycle exit and mitochondrial biogenesis. However, the pathophysiology remains to be fully described, and further characterization of the link between cell cycle regulation and mitochondrial function is needed. To this end we further assessed conditional erythroid-specific deletion of pRb. This resulted in macrocytic anemia, despite elevated levels of erythropoietin (Epo), and an accumulation of erythroid progenitors in the bone marrow, a phenotype strongly resembling refractory anemia associated with myelodysplastic syndromes (MDS). Using high-fractionation fluorescence-activated cell sorting analysis for improved phenotypic characterization, we illustrate that erythroid differentiation was disrupted at the orthochromatic stage. Transcriptional profiling of sequential purified populations revealed failure to upregulate genes critical for mitochondrial function such as Pgc1β, Alas2, and Abcb7 specifically at the block, together with disturbed heme production and iron transport. Notably, deregulated ABCB7 causes ring sideroblastic anemia in MDS patients, and the mitochondrial co-activator PGC1β is heterozygously lost in del5q MDS. Importantly, the anemia could be rescued through enhanced PPAR signaling in vivo via either overexpression of Pgc1β or bezafibrate administration. In conclusion, lack of pRb results in MDS-like anemia with disrupted differentiation and impaired mitochondrial function at the orthochromatic erythroblast stage. Our findings reveal for the first time a role for pRb in heme and iron regulation, and indicate that pRb-induced anemia can be rescued in vivo through therapeutic enhancement of PPAR signaling.</p>}}, author = {{Sen, Taha and Jain, Mayur and Gram, Magnus and Mattebo, Alexander and Soneji, Shamit and Walkley, Carl R. and Singbrant, Sofie}}, issn = {{0301-472X}}, language = {{eng}}, month = {{08}}, pages = {{28--41}}, publisher = {{Elsevier}}, series = {{Experimental Hematology}}, title = {{Enhancing mitochondrial function in vivo rescues MDS-like anemia induced by pRb deficiency}}, url = {{http://dx.doi.org/10.1016/j.exphem.2020.06.006}}, doi = {{10.1016/j.exphem.2020.06.006}}, volume = {{88}}, year = {{2020}}, }