Chromosome Condensation 1-Like (Chc1L) Is a Novel Tumor Suppressor Involved in Development of Histiocyte-Rich Neoplasms.
Human chromosomal region 13q14 is a deletion hotspot in prostate cancer, multiple myeloma, and chronic lymphocytic leukemia. This region is believed to host multiple tumor suppressors. Chromosome Condensation 1-like (CHC1L) is located at 13q14, and found within the smallest common region of loss of heterozygosity in prostate cancer. Decreased expression of CHC1L is linked to pathogenesis and progression of both prostate cancer and multiple myeloma. However, there is no direct evidence for CHC1L's putative tumor suppressing role in current literature. Presently, we describe the generation and characterization of Chc1L knockout mice. Chc1L-/- mice do not develop cancer at a young age, but bone marrow and spleen cells from 8-12 week-old mice display an exaggerated proliferative response. By approximately two years of age, knockout and heterozygote mice have a markedly increased incidence of tumorigenesis compared to wild-type controls, with tumors occurring mainly in the spleen, mesenteric lymph nodes, liver and intestinal tract. Histopathological analysis found that most heterozygote and knockout mice succumb to either Histiocytic Sarcoma or Histiocyte-Associated Lymphoma. Our study suggests that Chc1L is involved in suppression of these two histiocyte-rich neoplasms in mice and supports clinical data suggesting that CHC1L loss of function is an important step in the pathogenesis of cancers containing 13q14 deletion.
Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Medicine & Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
David R
DR
Spillane
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Ding Yan
DY
Wang
Centre for Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, The Toronto Centre for Phenogenomics, University of Toronto, Toronto, Ontario, Canada.
Susan
S
Newbigging
Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Youdong
Y
Wang
Department of Medicine & Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Chang-Xin
CX
Shi
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
Hae-Ra
HR
Cho
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
Hiroki
H
Shimizu
Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Anthony
A
Gramolini
Department of Medicine & Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
Mingyao
M
Liu
Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Medicine & Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Xiao-Yan
XY
Wen
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002872:Chromosome Deletion; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006644:Histiocytes / Q000473:pathology*; D019656:Loss of Heterozygosity / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D013154:Spleen / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C499302:Rcc1 protein, mouse; D025521:Tumor Suppressor Proteins