Widespread intronic polyadenylation inactivates tumor suppressor genes in leukemia

DNA mutations are known cancer drivers. Here, we investigated if mRNA events that are upregulated in cancer can functionally mimic the outcome of genetic alterations. 3′-seq or RNA-seq were applied to normal and malignant B cells from chronic lymphocytic leukemia (CLL; N = 59)(1–3). We discovered widespread upregulation of truncated mRNAs and proteins in primary CLL cells that were not generated by genetic alterations but occurred through intronic polyadenylation (IPA). IPA-generated truncated mRNAs were recurrent (N = 330) and predominantly affected genes with tumor-suppressive functions. The IPA-generated truncated proteins often lack the tumor-suppressive functions of the corresponding full-length proteins (DICER, FOXN3), and several even acted in an oncogenic manner (CARD11, MGA, CHST11). In CLL, inactivation of tumor-suppressor genes (TSGs) through aberrant mRNA processing is substantially more prevalent than loss of TSGs through genetic events. We further identified novel TSG candidates that are inactivated by IPA in leukemia and by truncating DNA mutations in solid tumors(4,5). These genes are understudied in cancer as their overall mutation rates are lower than those of well-known TSGs. Our findings show the need to go beyond genomic analyses in cancer diagnostics, as mRNA events that are silent at the DNA level are widespread contributors to cancer pathogenesis through inactivation of TSGs.