Genetically-determined myb insufficiency directly impacts on proteostasis in hematopoietic stem cells predisposing to age-related myeloid neoplasia

Acquired disturbances of signaling components in hematopoietic stem cells (HSC) are a feature of hematological neoplasia. Such driver mutations often require additional genetic or environmental influences to elicit transformation. Gene association studies reveal that some of these influences are natural inherited variants. Acquired genetic dysregulation of Myb, which plays a crucial role in HSC gene regulation, is directly involved in the etiology of a number of leukemias. Also, inherited non-coding variants of the Myb gene are a factor in susceptibility to many hematological conditions, including myeloproliferative neoplasms (MPN). Here, we show that Myb insufficiency in mice leads in later life to MPN, myelodysplasia, and leukemia, mirroring the age profile of equivalent human diseases. This age-dependence is intrinsic to HSC, involving progressive accumulation of subtle changes. Altered proteosomal activity in young Myb-insufficient mice and later elevated ribosome activity collectively cause an imbalance in proteostasis, potentially creating a cellular milieu favoring disease initiation by driver mutations.