Vardaka Panagiota, Kemp Ben, Stephenson Sophie, Page Eden, Care Matthew A, Umpierrez Michelle, Annahar Adam, O'Callaghan Eleanor, Owen Roger, Hodson Daniel J, Doody Gina M, Tooze Reuben M
Division of Haematology and Immunology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK.
Epidemiology and Cancer Statistics Group, Department of Health Sciences, University of York, York, UK.
Life Sci Alliance. 2025 Jul 28;8(10). doi: 10.26508/lsa.202402814. Print 2025 Oct.
MYC provides a rheostat linking cell growth and division. Deregulation of MYC drives transformation in aggressive B-cell neoplasms, often accompanied by BCL2-mediated apoptotic protection. We assess how MYC and BCL2 deregulation impacts on the ability of human B cells to complete plasma cell (PC) differentiation. As B cells differentiate, MYC deregulation has little impact on the regulatory circuitry controlling B-cell identity. Induction of transcriptional regulators BLIMP1 and IRF4 remains intact and accompanies loss of B-cell surface markers. However, such differentiating cells develop an aberrant surface phenotype with reduced expression of phenotypic markers of differentiation. Although functional antibody secretion is established, enforced MYC expression dampens the expression of secretory programmes associated with PC differentiation. Accompanying this, diverse changes in the expression of genes related to translation and metabolism are observed. The establishment of this aberrant differentiated state depends on MYC homology box II. This dependence is profound and resolves to residue W135.
MYC提供了一个连接细胞生长和分裂的变阻器。MYC失调驱动侵袭性B细胞肿瘤发生转化，常伴有BCL2介导的凋亡保护。我们评估MYC和BCL2失调如何影响人类B细胞完成浆细胞（PC）分化的能力。随着B细胞分化，MYC失调对控制B细胞特性的调控回路影响很小。转录调节因子BLIMP1和IRF4的诱导仍然完整，并伴随着B细胞表面标志物的丧失。然而，这种分化细胞会出现异常的表面表型，分化表型标志物的表达降低。尽管建立了功能性抗体分泌，但强制表达MYC会抑制与PC分化相关的分泌程序的表达。与此同时，观察到与翻译和代谢相关的基因表达发生了多种变化。这种异常分化状态的建立依赖于MYC同源框II。这种依赖性很强，可归结于第135位残基W。
