Distinct clinical and biological implications of CUX1 in myeloid neoplasms

Abstract

Somatic mutations of the CUT-like homeobox 1 (<i>CUX1</i>) gene (<i>CUX1</i> ^MT) can be found in myeloid neoplasms (MNs), in particular, in myelodysplastic syndromes (MDSs). The <i>CUX1</i> locus is also deleted in 3 of 4 MN cases with -7/del(7q). A cohort of 1480 MN patients was used to characterize clinical features and clonal hierarchy associated with <i>CUX1</i> ^MT and <i>CUX1</i> deletions (<i>CUX1</i> ^DEL) and to analyze their functional consequences in vitro. <i>CUX1</i> ^MT were present in 4% of chronic MNs. <i>CUX1</i> ^DEL were preferentially found in advanced cases (6%). Most MDS and acute myeloid leukemia (AML) patients with -7/del(7q) and up to 15% of MDS patients and 5% of AML patients diploid for the <i>CUX1</i> locus exhibited downmodulated CUX1 expression. In 75% of mutant cases, <i>CUX1</i> ^MT were heterozygous, whereas microdeletions and homozygous and compound-heterozygous mutations were less common. <i>CUX</i> ^MT/DEL were associated with worse survival compared with <i>CUX1</i> ^WT Within the clonal hierarchy, 1 of 3 <i>CUX1</i> ^MT served as founder events often followed by secondary <i>BCOR</i> and <i>ASXL1</i> subclonal hits, whereas <i>TET2</i> was the most common ancestral lesion, followed by subclonal <i>CUX1</i> ^MT Comet assay of patients' bone marrow progenitor cells and leukemic cell lines performed in various experimental conditions revealed that frameshift mutations, hemizygous deletions, or experimental <i>CUX1</i> knockdown decrease the repair of oxidized bases. These functional findings may explain why samples with either <i>CUX1</i> ^MT or low CUX1 expression coincided with significantly higher numbers of somatic hits by whole-exome sequencing. Our findings implicate the DNA repair dysfunction resulting from <i>CUX1</i> lesions in the pathogenesis of MNs, in which they lead to a mutator phenotype.