Themycproto-oncogenes encode nuclear DNA-binding phosphoproteins which regulate cell proliferation and differentiation. The c-mycgene is implicated in hematopoietic malignancies on the basis of its frequent deregulation in naturally occumng leukemias and lymphomas. Recent evidence suggests that also the N-mycand L-mycgenes may have a role in normal and malignant hematopoiesis. N-mycand to a certain degree L-myccan substitute for c-mycin transformation assaysin vitvo, and their overexpression can block the differentiation of leukemia cell lines. Immunoglobulin heavy chain enhancer (IgH)-driven overexpression of N-mycor L-mycgenes cause lymphatic and myeloid tumors, respectively, in transgenic mice. Furthermore, the L-mycand N-mycgenes are expressed in several human leukemias and leukemia cell lines, L-mycpredominantly in myeloid and N-mycboth in myeloid and in some lymphoid leukemias. All N/L-mycpositive leukemias and leukemia cell lines coexpress the c-mycgene, thus exemplifying a lack of negative cross-regulation between the differentmycgenes in leukemia cells. Taken together, these data suggest that L-mycand N-mycmay participate in the growth regulation of hematopoietic cells.