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

ABSTRACT

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.

KEYWORDS:

• Myelodysplastic syndrome
• hematopoietic stem cells
• PI3K/AKT
• autophagy
• self-renewal
• lysosome

Disclosure statement

The authors report no financial conflicts of interest.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by National Institutes of Health grants R01CA196973 (to K.G.), R56DK130895-01 (K.G.), R01DK130895-01 (K.G.), and NHLBI/NIH F32HL146119 (K.A.).