HSPA9/mortalin inhibition disrupts erythroid maturation through a TP53-dependent mechanism in human CD34+ hematopoietic progenitor cells

In this study, we explored the role of HSPA9 in regulating erythroid maturation using human CD34+ cells. We inhibited the expression of HSPA9 using gene knockdown and pharmacological inhibition, and found that inhibition of HSPA9 disrupted erythroid maturation as well as increased expression of p53 in CD34+ cells. To test whether the molecular mechanism of HSPA9 regulating erythroid maturation is TP53-dependent, we knocked-down HSPA9 and TP53 individually or in combination in human CD34+ cells. We found that knock-down of TP53 partially rescued the erythroid maturation defect induced by HSPA9 knock-down, suggesting that the defect in cells with reduced HSPA9 expression is TP53-dependent. Collectively, these findings indicate that reduced levels of HSPA9 may contribute to the anemia observed in del(5q)-associated MDS patients due to the activation of TP53. SIGNIFICANCE STATEMENT: MDS is the most common adult myeloid blood cancer in the United States. A typical symptom of MDS patients includes fatigue that is associated with anemia. Some MDS patients harbor del(5q), with haploinsufficiency for a set of genes including HSPA9. We showed that inhibition of HSPA9 disrupts erythroid maturation in human CD34+ hematopoietic progenitor cells, through a TP53-dependent mechanism. Our findings not only indicate that reduced levels of HSPA9 may contribute to anemia observed in del(5q)-associated MDS patients, but also provide new insights into potential mechanisms of anemia.PMID:38508444 |...
Source: Cell Stress and Chaperones - Category: Cytology Authors: Source Type: research