MYB insufficiency disrupts proteostasis in hematopoietic stem cells, leading to age-related neoplasia

MYB plays a key role in gene regulation throughout the hematopoietic hierarchy and is critical for the maintenance of normal hematopoietic stem cells (HSC). Acquired genetic dysregulation of MYB is involved in the etiology of a number of leukemias, although inherited noncoding variants of the MYB gene are a susceptibility factor for many hematological conditions, including myeloproliferative neoplasms (MPN). The mechanisms that connect variations in MYB levels to disease predisposition, especially concerning age dependency in disease initiation, are completely unknown. Here, we describe a model of Myb insufficiency in mice that leads to MPN, myelodysplasia, and leukemia in later life, mirroring the age profile of equivalent human diseases. We show that this age dependency is intrinsic to HSC, involving a combination of an initial defective cellular state resulting from small effects on the expression of multiple genes and a progressive accumulation of further subtle changes. Similar to previous studies showing the importance of pro-teostasis in HSC maintenance, we observed altered proteasomal activity and elevated proliferation indicators, followed by elevated ribosome activity in young Myb-insufficient mice. We propose that these alterations combine to cause an imbalance in proteostasis, potentially creating a cellular milieu favoring disease initiation.

Automated summary

MYB is crucial for gene regulation in hematopoietic hierarchy and maintaining normal hematopoietic stem cells (HSC). Genetic dysregulation of MYB is involved in leukemias, while inherited noncoding variants of MYB contribute to various hematological conditions. However, the mechanism linking MYB levels to disease predisposition, especially age-related disease initiation, remains unknown. Our mouse model of Myb insufficiency shows development of MPN, myelodysplasia, and leukemia in later life, mimicking the age profile of human diseases. In young Myb-insufficient mice, we observe altered proteasomal activity and elevated proliferation indicators, suggesting an imbalance in proteostasis contributing to disease initiation.