Unraveling the Link between Class 1A PI3-Kinase, Autophagy, and Myelodysplasia

Myelodysplastic syndrome (MDS) is a clonal malignancy that develops from hematopoietic stem cells (HSCs), but the underlying mechanisms of MDS initiation are not well understood. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is often dysregulated in MDS. To investigate how PI3K inactivation affects HSC function, we generated a mouse model in which three Class IA PI3K genes were deleted in hematopoietic cells. Surprisingly, PI3K deficiency caused cytopenias, reduced survival, and multilineage dysplasia with chromosomal abnormalities, consistent with MDS initiation. PI3K-deficient HSCs had impaired autophagy, and pharmacologic treatment with autophagy-inducing reagents improved HSC differentiation. Furthermore, a similar autophagic degradation defect was observed in MDS patient HSCs. Therefore, our study uncovered a crucial protective role for Class IA PI3K in maintaining autophagic flux in HSCs to preserve the balance between self-renewal and differentiation.

Automated summary

Myelodysplastic syndrome (MDS) is a clonal malignancy that arises from hematopoietic stem cells (HSCs), and dysregulation of the PI3K/AKT pathway is often observed in MDS. In this study, a mouse model with PI3K deficiency in hematopoietic cells was generated to investigate the impact of PI3K inactivation on HSC function. The results showed that PI3K deficiency caused cytopenias, reduced survival, and multilineage dysplasia with chromosomal abnormalities, resembling MDS initiation. Additionally, impaired autophagy was observed in PI3K-deficient HSCs, and treatment with autophagy-inducing reagents improved HSC differentiation. Similar autophagic degradation defects were also found in MDS patient HSCs, suggesting a crucial protective role of Class IA PI3K in maintaining autophagic flux in HSCs for the preservation of self-renewal and differentiation balance.