Transcriptional profiling of polycythemia vera identifies gene expression patterns both dependent and independent from the action of JAK2V617F.
OBJECTIVE
To understand the changes in gene expression in polycythemia vera (PV) progenitor cells and their relationship to JAK2V617F.


METHODS
Messenger RNA isolated from CD34(+) cells from nine 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 reverse transcription-PCR, 23 genes were consistently deregulated in all patient samples. Several of these genes such as WT1 and KLF4 were regulated by JAK2, whereas others such as NFIB and EVI1 seemed 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 14 JAK2-dependent genes and 12 JAK2-independent genes. These two 14- and 12-gene sets could separate not only PV from normal CD34(+) specimens, but also other MPN such as essential thrombocytosis and primary myelofibrosis 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.
Berkofsky-Fessler
Windy
W
Translational Research Sciences, Hoffmann-La Roche, Inc., Nutley, NJ, USA.
Buzzai
Monica
M
Kim
Marianne K-H
MK
Fruchtman
Steven
S
Najfeld
Vesna
V
Min
Dong-Joon
DJ
Costa
Fabricio F
FF
Bischof
Jared M
JM
Soares
Marcelo B
MB
McConnell
Melanie Jane
MJ
Zhang
Weijia
W
Levine
Ross
R
Gilliland
D Gary
DG
Calogero
Raffaele
R
Licht
Jonathan D
JD
D019943:Amino Acid Substitution; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016000:Cluster Analysis; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011087:Polycythemia Vera / Q000097:blood / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D018952:Antigens, CD34; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D004921:Erythropoietin; D053614:Janus Kinase 2