Getting to know JAK.

摘要

This proposal is convincingly backed by the following experimental evidence: (1) plasma TNF-alpha levels are significantly higher in patients with myelofibrosis, polycy-themia vera, and essential thrombocythemia than in normal donors; (2) TNF-a levels in plasma correlate with JAK2~(V617F) allele burden, and TNF-a mRNA levels in HEL cells, ho-mozygous for JAK2~(V617F) with multiple copies of this gene, are increased compared with wild-type JAK2 lines; (3) myeloid progenitors from JAK2~(V617F) patients are less sensitive to (or even, insensitive to) TNF-a inhibition of proliferation in vitro than are progenitors from normal individuals, and non-JAK2~(V617F) progenitors are suppressed in the same patient samples containing JAK2~(V617F)-expressing progenitor clones not suppressed by TNF-a; in fact, JAK2~(V617F) granulocyte-macrophage progenitors are enhanced and erythroid progenitors are relatively resistant to TNF-a suppression in vitro; and (4) Fancc~(-/-) mouse bone marrow progenitor cells, known to be hyper-responsive to inhibition of proliferation in vitro by TNF-alpha, are protected from this effect by ectopic expression of JAK2~(V617F) in Fancc~(-/-) progenitors; moreover, cells harvested from 5-FU-treated TNF-alpha~(+/+), but not TNF-a"'", mice transduced with a JAK2~(V617F)-GFP retroviral vector and then transplanted into lethally irradiated syngeneic recipients, manifest disease burden increases.