The long (q) arm of chromosome 5 is highly enriched in Wnt signaling genes. (A) The location of genes on chromosome 5 encoding proteins within the Wnt signaling pathway. Dashed horizontal lines indicate the segment typically deleted in myeloid neoplasms with a del(5q). Green and red text identifies genes encoding known negative and positive regulators of Wnt/CTNNB1 activity, respectively. Blue text identifies CTNNB1 target genes. (B) Wnt signaling pathway illustrating that del(5q) genes encode multiple negative (green) or positive (red) key regulators of Wnt signaling. CTNNB1 target genes on 5q are identified in blue text. DVL (orange) maps to 17p13.1, a region commonly lost in del(5q) t-MN. (C) Color-coded heat maps of significantly (FDR < 0.2) downregulated (green) or upregulated (red) WNT signaling pathway genes (Kyoto Encyclopedia of Genes and Genomes) in t-MN patients with a del(5q) (n = 10) vs non-del(5q) (n = 28) (GSE39991). In both groups, one-third of patients had t-MDS, and two-thirds had t-AML. TP53 deletion and/or mutations were detected in 9/10 (90%) del(5q) and 3/25 (12%) non-del(5q) patients. Abnormalities of chromosome 7 were detected in 5/10 (50%) del(5q) and 9/28 (32%) non-del(5q) patients. The non-del(5q) group included patients with +8 (2/28; 7%), KMT2A/MLL (4/28; 14%), or RUNX1 (2/28, 7%) translocations, and other complex karyotypes (8/29; 28%). Three patients had a normal karyotype. The downregulation of genes encoding negative (green) and upregulation of positive (red) Wnt pathway regulators in del(5q) patients is consistent with an active Wnt signature. Genes on chromosome 5 are underlined.