MYBL2 haploinsufficiency increases susceptibility to age-related haematopoietic neoplasia.
The haematopoietic system is prone to age-related disorders ranging from deficits in functional blood cells to the development of neoplastic states. Such neoplasms often involve recurrent cytogenetic abnormalities, among which a deletion in the long arm of chromosome 20 (del20q) is common in myeloid malignancies. The del20q minimum deleted region contains nine genes, including MYBL2, which encodes a key protein involved in the maintenance of genome integrity. Here, we show that mice expressing half the normal levels of Mybl2 (Mybl2(+/Δ)) develop a variety of myeloid disorders upon ageing. These include myeloproliferative neoplasms, myelodysplasia (MDS) and myeloid leukaemia, mirroring the human conditions associated with del20q. Moreover, analysis of gene expression profiles from patients with MDS demonstrated reduced levels of MYBL2, regardless of del20q status and demonstrated a strong correlation between low levels of MYBL2 RNA and reduced expression of a subset of genes related to DNA replication and checkpoint control pathways. Paralleling the human data, we found that these pathways are also disturbed in our Mybl2(+/Δ) mice. This novel mouse model, therefore, represents a valuable tool for studying the initiation and progression of haematological malignancies during ageing, and may provide a platform for preclinical testing of therapeutic approaches.
Institute of Biomedical Research, Immunity and Infection Department, Birmingham University School of Medical and Dental Science, Edgbaston, Birmingham, UK.
M
M
Clarke
S
S
Dumon
C
C
Ward
R
R
Jäger
S
S
Freeman
B
B
Dawood
L
L
Sheriff
M
M
Lorvellec
R
R
Kralovics
J
J
Frampton
P
P
García
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D049109:Cell Proliferation; D018450:Disease Progression; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D019337:Hematologic Neoplasms / Q000209:etiology* / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*
D018797:Cell Cycle Proteins; C064352:MYBL2 protein, human; C499306:Mybl2 protein, mouse; D012333:RNA, Messenger; D015534:Trans-Activators