Genetic signature of histiocytic sarcoma revealed by a sleeping beauty transposon genetic screen in mice.
Histiocytic sarcoma is a rare, aggressive neoplasm that responds poorly to therapy. Histiocytic sarcoma is thought to arise from macrophage precursor cells via genetic changes that are largely undefined. To improve our understanding of the etiology of histiocytic sarcoma we conducted a forward genetic screen in mice using the Sleeping Beauty transposon as a mutagen to identify genetic drivers of histiocytic sarcoma. Sleeping Beauty mutagenesis was targeted to myeloid lineage cells using the Lysozyme2 promoter. Mice with activated Sleeping Beauty mutagenesis had significantly shortened lifespan and the majority of these mice developed tumors resembling human histiocytic sarcoma. Analysis of transposon insertions identified 27 common insertion sites containing 28 candidate cancer genes. Several of these genes are known drivers of hematological neoplasms, like Raf1, Fli1, and Mitf, while others are well-known cancer genes, including Nf1, Myc, Jak2, and Pten. Importantly, several new potential drivers of histiocytic sarcoma were identified and could serve as targets for therapy for histiocytic sarcoma patients.
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota, United States of America; Department of Comparative and Molecular Biosciences, University of Minnesota, St. Paul, Minnesota, United States of America.
Raha A
RA
Been
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America.
Michael A
MA
Linden
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
Courtney J
CJ
Hager
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
Krista J
KJ
DeCoursin
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
Juan E
JE
Abrahante
Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America.
Sean R
SR
Landman
Department of Computer Science and Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America.
Michael
M
Steinbach
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.
Aaron L
AL
Sarver
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, United States of America.
David A
DA
Largaespada
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America; Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, Minnesota, United States of America; Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, United States of America.
Timothy K
TK
Starr
D000818:Animals; D019070:Cell Lineage / Q000235:genetics; D004251:DNA Transposable Elements / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D054747:Histiocytic Sarcoma / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009113:Muramidase / Q000235:genetics; D016254:Mutagenesis, Insertional / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics
D004251:DNA Transposable Elements; D009113:Muramidase