Retroviral integration mutagenesis in mice and comparative analysis in human AML identify reduced PTP4A3 expression as a prognostic indicator.
Acute myeloid leukemia (AML) results from multiple genetic and epigenetic aberrations, many of which remain unidentified. Frequent loss of large chromosomal regions marks haplo-insufficiency as one of the major mechanisms contributing to leukemogenesis. However, which haplo-insufficient genes (HIGs) are involved in leukemogenesis is largely unknown and powerful experimental strategies aimed at their identification are currently lacking. Here, we present a new approach to discover HIGs, using retroviral integration mutagenesis in mice in which methylated viral integration sites and neighbouring genes were identified. In total we mapped 6 genes which are flanked by methylated viral integration sites (mVIS). Three of these, i.e., Lrmp, Hcls1 and Prkrir, were up regulated and one, i.e., Ptp4a3, was down regulated in the affected tumor. Next, we investigated the role of PTP4A3 in human AML and we show that PTP4A3 expression is a negative prognostic indicator, independent of other prognostic parameters. In conclusion, our novel strategy has identified PTP4A3 to potentially have a role in AML, on one hand as a candidate HIG contributing to leukemogenesis in mice and on the other hand as a prognostic indicator in human AML.
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Renée
R
Beekman
Marijke
M
Valkhof
Stefan J
SJ
Erkeland
Erdogan
E
Taskesen
Veronika
V
Rockova
Justine K
JK
Peeters
Peter J M
PJ
Valk
Bob
B
Löwenberg
Ivo P
IP
Touw
D000818:Animals; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D057895:Haploinsufficiency / Q000235:genetics; D006801:Humans; D009052:Leukemia Virus, Murine / Q000235:genetics / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000821:virology; D051379:Mice; D008875:Middle Aged; D016296:Mutagenesis; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D016662:Virus Integration / Q000235:genetics*
D009363:Neoplasm Proteins; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases