Declined presentation Role of MYBL2 haploinsufficiency in the development of age-related myeloid malignancies

Monoallelic deletion of the long arm of chromosome 20 (del20q) is observed in 5-10% of patients suffering from haematological disorders related to ageing, including myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN) and leukaemias. The minimum common deleted region published so far contains 9 genes. One of these genes is MYBL2, which codes for a transcription factor protein with a role in cell proliferation, DNA replication, genome stability maintenance and senescence. We generated a mouse model with monoallelic deletion of Mybl2 (Mybl2+/Δ), hence expressing half the normal dose of MYBL2. During ageing, Mybl2 haploinsufficient mice developed haematological disorders, including MDS, MPN and leukaemia, mimicking the human conditions associated with del20q (Clarke et al., Leukemia, 2012). We hypothesize that when MYBL2 levels are reduced, haematopoietic stem cells (HSC) are impaired in their ability to preserve their genome integrity, leading to accumulation of DNA damage and somatic mutations which drive the development of myeloid malignancies. To directly test this, we quantified DNA damage in HSC from Mybl2+/Δ and Mybl2+/+ mice following exposure to ionizing radiation (IR), which causes double strand DNA breaks (DSB) and global activation of the DNA damage response pathway. Our analysis revealed that Mybl2 haploinsufficient HSC display higher levels of DSB compared to wild-type cells. Consistent with this, gene expression analysis suggests that there is deregulated expression of key DNA damage response genes in Mybl2+/Δ HSC compared with Mybl2+/+ HSC. Mybl2 haploinsufficient HSC displayed decreased in vitro stem cell function in colony-forming cell assays upon exposure to IR, compared with HSC expressing wild-type levels of MYBL2. Our results suggest that Mybl2 haploinsufficiency is associated with attenuation of the DNA damage and repair response in HSC; this leads to DNA damage accumulation and provides a potential mechanism by which Mybl2 haploinsufficiency may cause haematopoietic neoplasia. Monoallelic deletion of the long arm of chromosome 20 (del20q) is observed in 5-10% of patients suffering from haematological disorders related to ageing, including myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN) and leukaemias. The minimum common deleted region published so far contains 9 genes. One of these genes is MYBL2, which codes for a transcription factor protein with a role in cell proliferation, DNA replication, genome stability maintenance and senescence. We generated a mouse model with monoallelic deletion of Mybl2 (Mybl2+/Δ), hence expressing half the normal dose of MYBL2. During ageing, Mybl2 haploinsufficient mice developed haematological disorders, including MDS, MPN and leukaemia, mimicking the human conditions associated with del20q (Clarke et al., Leukemia, 2012). We hypothesize that when MYBL2 levels are reduced, haematopoietic stem cells (HSC) are impaired in their ability to preserve their genome integrity, leading to accumulation of DNA damage and somatic mutations which drive the development of myeloid malignancies. To directly test this, we quantified DNA damage in HSC from Mybl2+/Δ and Mybl2+/+ mice following exposure to ionizing radiation (IR), which causes double strand DNA breaks (DSB) and global activation of the DNA damage response pathway. Our analysis revealed that Mybl2 haploinsufficient HSC display higher levels of DSB compared to wild-type cells. Consistent with this, gene expression analysis suggests that there is deregulated expression of key DNA damage response genes in Mybl2+/Δ HSC compared with Mybl2+/+ HSC. Mybl2 haploinsufficient HSC displayed decreased in vitro stem cell function in colony-forming cell assays upon exposure to IR, compared with HSC expressing wild-type levels of MYBL2. Our results suggest that Mybl2 haploinsufficiency is associated with attenuation of the DNA damage and repair response in HSC; this leads to DNA damage accumulation and provides a potential mechanism by which Mybl2 haploinsufficiency may cause haematopoietic neoplasia.