Purpose: To understand the changes in gene expression in PV progenitor cells and their relationship to JAK2V617F Experimental Design: mRNA isolated from CD34+ cells from 9 PV patients and normal controls was profiled using Affymetrix arrays. Gene expression change mediated by JAK2V617F was determined by profiling CD34+ cells transduced with the kinase and by analysis of leukemia cell lines harboring JAK2V617F, treated with an inhibitor. Results: A PV expression signature was enriched for genes involved in hematopoietic development, inflammatory responses and cell proliferation. By quantitative RT-PCR, 23 genes were consistently deregulated in all patient samples. Several of these genes such as WT1 and KLF4 were regulated by JAK2, while others such as NFIB and EVI1 appeared to be deregulated in PV by a JAK2 independent mechanism. Using cell line models and comparing gene expression profiles of cell lines and PV CD34+ PV specimens, we have identified panels of JAK2 dependent 14 genes and JAK2 independent 12 genes. These two 14 and 12 gene sets could separate not only PV from normal CD34+ specimens, but also other MPN such as ET and MF from their normal counterparts. Conclusions: A subset of the aberrant gene expression in PV progenitor cells can be attributed to the action of the mutant kinase, but there remain a significant number of genes characteristic of the disease but deregulated by as yet unknown mechanisms. Genes deregulated in PV as a result of the action of JAK2V617F or independent of the kinase may represent other targets for therapy.
- Received April 29, 2010.
- Revision received June 5, 2010.
- Accepted June 30, 2010.