Enforced MYC expression selectively redirects transcriptional programs during human plasma cell differentiation

MYC provides a rheostat linking cell growth and division during plasma cell (PC) differentiation. Precise control of MYC is central to the network controlling differentiation. Deregulation of MYC drives transformation in aggressive B-cell neoplasms and is often accompanied by apoptotic protection conferred by BCL2. We assess how MYC and BCL2 deregulation impacts on the ability of human B-cells to complete PC differentiation. Under permissive conditions for PC differentiation we find such deregulation does not transform cells. While driving loss of normal PC surface phenotype, MYC deregulation has little impact on components of regulatory circuitry controlling B-cell identity. This contrasts with profound impact on initiation of secretory output and secretory reprogramming, coupled to dampening of XBP1 and immunoglobulin gene enhancement and a shift toward distinct metabolic programs. The establishment of this aberrant state depends on MYC homology boxes (MB0 and MBII). Dependence on MBII is profound and resolves to residue W135.