Elevated CDKN1a (p21) mediates β-thalassemia erythroid apoptosis but its loss does not improve β-thalassemic erythropoiesis.
Raymond LiangMiao LinVijay MenonJiajing QiuAnagha MenonLaura BredaTasleem ArifStefano RivellaSaghi GhaffariPublished in: Blood advances (2023)
β-thalassemias are common hemoglobinopathies due to mutations in the β-globin gene that lead to hemolytic anemias. Premature death of β-thalassemic erythroid precursors results in ineffective erythroid maturation, increased production of erythropoietin (Epo), expansion of erythroid progenitor compartment, extramedullary erythropoiesis and splenomegaly. However, the molecular mechanism of erythroid apoptosis in β-thalassemia is not well understood. Using a mouse model of β-thalassemia (Hbbth3/+), we show that dysregulated expression of Foxo3 transcription factor is implicated in β-thalassemia erythroid apoptosis. In Foxo3-/-/Hbbth3/+ mice, erythroid apoptosis is significantly reduced, while erythroid cell maturation, red blood cell and hemoglobin production are substantially improved and reactive oxygen species (ROS) are elevated in double mutant erythroblasts. However, persistence of elevated reticulocytes and splenomegaly suggests that ineffective erythropoiesis is not resolved in Foxo3-/-/Hbbth3/+. Next, we showed that the Foxo3 target cell cycle inhibitor Cdkn1a (p21) is markedly upregulated in both mouse and patients-derived β-thalassemic erythroid precursors. Double mutant p21/Hbbth3/+ mice exhibited embryonic lethality with only a fraction of mice surviving to weaning. Notably, studies in adult mice showed apoptosis and circulating Epo were greatly reduced in erythroid compartments of surviving p21-/-/Hbbth3/+ relative to Hbbth3/+ mice, while ineffective erythroid cell maturation, extramedullary erythropoiesis and splenomegaly were not modified. These combined results suggest that mechanisms that control β-thalassemic erythroid cell survival and differentiation are uncoupled from ineffective erythropoiesis and involve a molecular network including FOXO3 and p21. Overall, these studies provide a new framework for investigating ineffective erythropoiesis in β-thalassemia.
Keyphrases
- transcription factor
- oxidative stress
- endoplasmic reticulum stress
- cell cycle
- cell death
- cell cycle arrest
- reactive oxygen species
- red blood cell
- signaling pathway
- cell proliferation
- type diabetes
- gene expression
- poor prognosis
- cell therapy
- intensive care unit
- skeletal muscle
- adipose tissue
- bone marrow
- young adults
- acute respiratory distress syndrome
- long non coding rna
- copy number
- single molecule
- case control
- genome wide identification
- genome wide