Credit: Aaron Logan
Scientists have found that a single cell containing the JAK2-V617F mutation can cause myeloproliferative neoplasms (MPNs) in mice.
The team isolated hematopoietic stem cells (HSCs) from malignant MPNs and transplanted a single cell with mutated JAK2 into groups of healthy mice.
A subset of the mice developed MPNs, which also bore the JAK2 mutation.
The researchers described this work in The Journal of Experimental Medicine.
Pontus Lundberg, PhD, of University Hospital Basel in Switzerland, and his colleagues performed several sets of experiments in which they transplanted JAK2-V617F-expressing cells in dilutions of wild-type bone marrow cells.
In the 1:125 dilution experiment, 24% of mice (4/17) developed polycythemia vera (PV). In the 1:250 dilution experiment, 44% of mice developed either PV or essential thrombocythemia (ET).
The researchers were interested to find that erythrocytosis and thrombocytosis were mutually exclusive in individual mice.
Additional investigation revealed that MPN development did not depend on the acquisition of additional somatic mutations.
To confirm their findings, the researchers then transplanted a single JAK2-V617F-expressing HSC into a total of 113 mice in 4 independent experiments.
Only 1 mouse developed an ET phenotype. Two other mice had transient high chimerism in erythrocytes and/or platelets, but they did not develop ET or PV.
Furthermore, transplanting bone marrow from the mouse with the ET phenotype into secondary recipients did not result in an MPN phenotype.
The researchers also analyzed JAK2-V617F-expressing HSCs in further detail, and they found these HSCs promoted cell division and increased DNA damage.
Higher JAK2-V617F expression was associated with a short-term HSC signature and increased myeloid bias. Lower JAK2-V617F expression was associated with the capacity to stably engraft in secondary recipients.
Dr Lundberg and his colleagues said this research shows that JAK2-V617F has complex effects on HSC biology and that MPNs can develop from a single JAK2-V617F-expressing cell.
