Enhancing mitochondrial function in vivo rescues MDS-like anemia induced by pRb deficiency

Taha Sen, Mayur Jain, Magnus Gram, Alexander Mattebo, Shamit Soneji, Carl R. Walkley, Sofie Singbrant

Research output: Contribution to journalArticlepeer-review

3 Citations (SciVal)

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 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.

Original languageEnglish
Pages (from-to)28-41
Number of pages14
JournalExperimental Hematology
Volume88
Early online date2020 Jul 3
DOIs
Publication statusPublished - 2020 Aug 1

Subject classification (UKÄ)

  • Hematology
  • Cell and Molecular Biology

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