The stem/progenitor landscape is reshaped in a mouse model of essential thrombocythemia and causes excess megakaryocyte production.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 33239297.
- Also identified by DOI 10.1126/sciadv.abd3139 and PMC identifier 7688335.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Frameshift mutations in <i>CALR</i> (calreticulin) are associated with essential thrombocythemia (ET), but the stages at and mechanisms by which mutant CALR drives transformation remain incompletely defined. Here, we use single-cell approaches to examine the hematopoietic stem/progenitor cell landscape in a mouse model of mutant CALR-driven ET. We identify a trajectory linking hematopoietic stem cells (HSCs) with megakaryocytes and prospectively identify a previously unknown intermediate population that is overrepresented in the disease state. We also show that mutant CALR drives transformation primarily from the earliest stem cell compartment, with some contribution from megakaryocyte progenitors. Last, relative to wild-type HSCs, mutant CALR HSCs show increases in JAK-STAT signaling, the unfolded protein response, cell cycle, and a previously undescribed up-regulation of cholesterol biosynthesis. Overall, we have identified a novel megakaryocyte-biased cell population that is increased in a mouse model of ET and described transcriptomic changes linking <i>CALR</i> mutations to increased HSC proliferation and megakaryopoiesis.