JAK2V617F Mutant Megakaryocytes Contribute to Hematopoietic Aging in a Murine Model of Myeloproliferative Neoplasm

Area of Science:

• Hematology
• Stem Cell Biology
• Oncology

Background:

• Megakaryocytes (MKs) are crucial components of the hematopoietic niche.
• Abnormal MK hyperplasia is a key characteristic of myeloproliferative neoplasms (MPNs).
• The JAK2V617F mutation is frequently found in hematopoietic cells of MPN patients.

Purpose of the Study:

• To investigate the role of JAK2V617F-bearing MKs in hematopoietic stem cell (HSC) aging within an MPN context.
• To elucidate the mechanisms by which mutated MKs influence the hematopoietic stem cell niche and HSC function.

Main Methods:

• Utilized a murine model expressing the human JAK2V617F gene in the MK lineage.
• Assessed HSC aging phenotypes, including myeloid-skewed hematopoiesis, engraftment capacity, self-renewal, and differentiation.
• Analyzed the hematopoietic niche microenvironment through MK-HSC interactions, vascular niche function, RNA expression profiling, and cytokine arrays.

Main Results:

• JAK2V617F-bearing MKs promote HSC aging, leading to myeloid-biased hematopoiesis and reduced HSC engraftment and self-renewal.
• HSCs from affected mice exhibited increased proliferation and reduced quiescence compared to controls.
• Mutated MKs altered the hematopoietic niche by decreasing direct interactions with HSCs, suppressing vascular niche function, and increasing pro-inflammatory and anti-angiogenic factors.

Conclusions:

• JAK2V617F-bearing MKs are significant drivers of HSC aging in MPNs.
• MKs serve as a critical link between extrinsic and intrinsic mechanisms regulating HSC aging.
• Targeting JAK2V617F-expressing MKs may offer therapeutic strategies for MPNs and age-related hematopoietic dysfunction.