Novel nuclear receptor coactivator is a candidate for the del(5q) Leukemia tumor suppressor gene

Interstitial deletion or loss of chromosome 5 is frequent in myeloid leukemias and dysplasias, suggesting the presence of a tumor suppressor gene (TSG) within the consistently-deleted region at 5q31. We report a novel gene at 5q31, 5qNCA, as a candidate for this TSG. 5qNCA spans 23 exons and produces a 7.4-kb transcript with a 5,286-kb open reading frame that is expressed in heart, skeletal muscle, lung, and placenta as well as CD34+ cells and AML cell lines. The gene contains a highly conserved C-terminus with putative transcriptional regulatory activity, a signature motif for a nuclear receptor co-activator, and a zinc finger (ZF). 5qNCA is homologous to TRIP8, human/murine hairless, KIAA0742, and drosophila CG815 in the ZF and transactivation domains. The ZF has the unique spacing CysX2-Cys-X7-His-X2-Cys-X2-Cys-X4-Cys-X2-Cys, which may define a new family, resembling both LIM and PHD ZF domains, which regulate chromatin structure and are often involved in leukemia. KG-1, an AML cell line with del(5q), shows a mutation in exon 6 resulting in a THR to ALA substitution of unknown significance; additional sequencing is in progress in clinical del(5q) samples. We propose 5qNCR as a likely candidate for the del(5q) TSG based on its protein homologies, expression, and mutation.