Neutrophil Serine Proteases: Future Therapeutic Targets in Patients with Severe Chronic Neutropenia and Leukemia?

Garwicz, Daniel

doi:10.1634/stemcells.2005-0584

Cited by 1 publication

(1 citation statement)

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“…Members of the hematopoietic serine protease superfamily that activate PARs, such as cathepsin G, neutrophile elastase and proteinase 3, may play an important role in myeloid biology [37]. Patients, who suffer from hematological disorder or congenital neutropenia frequently exhibit mutations in genes for neutrophil serine-proteases or show alterations in its expression, localisation or activity [38].…”

Section: Discussionmentioning

confidence: 99%

Proteinase-Activated Receptor 1 (PAR1) Regulates Leukemic Stem Cell Functions

Bäumer

Krause

Köhler³

et al. 2014

PLoS ONE

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External signals that are mediated by specific receptors determine stem cell fate. The thrombin receptor PAR1 plays an important role in haemostasis, thrombosis and vascular biology, but also in tumor biology and angiogenesis. Its expression and function in hematopoietic stem cells is largely unknown. Here, we analyzed expression and function of PAR1 in primary hematopoietic cells and their leukemic counterparts. AML patients' blast cells expressed much lower levels of PAR1 mRNA and protein than CD34+ progenitor cells. Constitutive Par1-deficiency in adult mice did not affect engraftment or stem cell potential of hematopoietic cells. To model an AML with Par1-deficiency, we retrovirally introduced the oncogene MLL-AF9 in wild type and Par1−/− hematopoietic progenitor cells. Par1-deficiency did not alter initial leukemia development. However, the loss of Par1 enhanced leukemic stem cell function in vitro and in vivo. Re-expression of PAR1 in Par1−/− leukemic stem cells delayed leukemogenesis in vivo. These data indicate that Par1 contributes to leukemic stem cell maintenance.

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Section: Discussionmentioning

confidence: 99%