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Adhesion to Fibronectin via α5β1 Integrin Supports Expansion of Megakaryocyte Lineage in Primary Myelofibrosis

By April 24, 2020No Comments

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This week we profile a recent publication in Blood from Dr. Shinobu Matsuura (pictured, left)
in the laboratory of Dr. Katya Ravid (right) at the Boston University School of Medicine.

Can you provide a brief overview of your lab’s current research focus?

The laboratory of Professor Katya Ravid at Boston University School of Medicine studies the development of hematopoietic cells in health and disease, with a focus on the megakaryocyte/platelet lineage. The group investigates mechanisms by which this lineage propagates to contribute the primary myelofibrosis (PMF), and how the bone marrow matrix is sensed to elicit effects on megakaryocyte and platelet development. A related line of investigations centers on the mechanism by which bone marrow cell malignancy, such as PMF, contributes to increased propensity for thrombosis and cardiovascular disease.

What is the significance of the findings in this publication?

In a recent Blood paper, the Ravid laboratory, with Dr. Shinobu Matsuura as first author, discovered that the megakaryocyte integrin alpha5 is significantly upregulated in PMF, induced by a JAK2V617F+ mutation in mice. Importantly, the alpha5-fibronectin axis was identified as a new pathway by which the megakaryocytic lineage senses the bone marrow matrix to expand cell number in this pathology. Antibody-mediated inhibition of both alpha5 integrin binding and megakaryocyte adhesion to fibronectin reduced the burden of megakaryocyte number in this pathology. In collaboration with Dr. Alessandra Balduini, findings were also confirmed in human samples of the disease.

What are the next steps for this research?

The next step would be to test this paradigm therapeutically, as well as focus on possible effects of inhibiting the alpha5-fibronectin-extracellular matrix axis on bone marrow fibrosis and/or changes in thrombosis associated with PMF.

This work was funded by:

This study was supported mainly by NIH NHLBI grant R01HL136363 to Dr. Ravid. Other support included: Associazione Italiana per la Ricerca sul Cancro: AIRC IG 2016 18700 to AB and Italian Ministry of Health (Ricerca Finalizzata Giovani Ricercatori GR-2016-02363136) to AB. SM is supported by the NIH ORIP SERCA K01 award 1K01_D025290-01A1.

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