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, while inherited non-coding variants of the MYB gene are a factor in susceptibility to many hematological conditions, including myeloproliferative neoplasms (MPN). The mechanisms that connect variations in MYB levels to disease predisposition, especially in relation to age-dependency in disease initiation, are completely unknown. Here, we describe a model of Myb insufficiency in mice that leads in later life to MPN, myelodysplasia, and leukemia, mirroring the age profile of equivalent human diseases. We show that this age-dependence 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. Linking to previous studies showing the importance of proteostasis in HSC maintenance, we observed altered proteosomal activity in young Myb-insufficient mice as well as elevated proliferation indicators, followed later by elevated ribosome activity. We propose that these alterations combine to cause an imbalance in proteostasis, potentially creating a cellular milieu favoring disease initiation.