Hyperfunctioning MYC selectively redirects expression programs during human plasma cell differentiation I

MYC acts as a rheostat during plasma cell (PC) differentiation, linking B-cell activation to cell growth and division. Tight control over MYC is an essential feature of the network controlling differentiation. Deregulation of MYC is common in aggressive B-cell neoplasms, driving cellular transformation, and is often accompanied by apoptotic protection conferred by BCL2. Here we assess how acutely enforced MYC and BCL2 deregulation impacts on the ability of human B-cells to complete PC differentiation. In the context of a permissive state for PC differentiation such acute deregulation does not suffice to transform human B-cells. Instead MYC drives a sequence of metabolic and growth-related expression programs while suppressing the transition to immunoglobulin secretion and thus establishes an aberrant differentiation state. The ability of MYC to establish this aberrant state depends on MB0 and MBII of its transactivation domain. Dependence on MBII is profound and can be resolved to conserved residue W135. Overall design: RNA-seq profiles of human naïve B-cells differentiated from day 0 to day 20 plasma cells, from 3-4 healthy donors, with transductions of retroviral constructs that explored MYC/BCL2 overexpression in the context of different MYC mutations.