Myc stimulates B lymphocyte differentiation and amplifies calcium signaling

Deregulated expression of the Myc family of transcription factors (c-, N-, and L-myc) contributes to the development of many cancers by a mechanism believed to involve the stimulation of cell proliferation and inhibition of differentiation. However, using B cell-specific c-/N-myc double-knockout mice and Eμ-myc transgenic mice bred onto genetic backgrounds (recombinase- activating gene 2^-/- and Btk^-/- Tec^-/-) whereby B cell development is arrested, we show that Myc is necessary to stimulate both proliferation and differentiation in primary B cells. Moreover, Myc expression results in sustained increases in intracellular Ca²⁺ ([Ca ²⁺]_i), which is required for Myc to stimulate B cell proliferation and differentiation. The increase in [Ca²⁺]_i correlates with constitutive nuclear factor of activated T cells (NFAT) nuclear translocation, reduced Ca²⁺ efflux, and decreased expression of the plasma membrane Ca²⁺-adenosine triphosphatase (PMCA) efflux pump. Our findings demonstrate a revised model whereby Myc promotes both proliferation and differentiation, in part by a remarkable mechanism whereby Myc amplifies Ca²⁺ signals, thereby enabling the concurrent expression of Myc- and Ca²⁺-regulated target genes.