Genomics of deletion 7 and 7q in myeloid neoplasm: from pathogenic culprits to potential synthetic lethal therapeutic targets

Abstract

Complete or partial deletions of chromosome 7 (-7/del7q) belong to the most frequent chromosomal abnormalities in myeloid neoplasm (MN) and are associated with a poor prognosis. The disease biology of -7/del7q and the genes responsible for the leukemogenic properties have not been completely elucidated. Chromosomal deletions may create clonal vulnerabilities due to haploinsufficient (HI) genes contained in the deleted regions. Therefore, HI genes are potential targets of synthetic lethal strategies. Through the most comprehensive multimodal analysis of more than 600 -7/del7q MN samples, we elucidated the disease biology and qualified a list of most consistently deleted and HI genes. Among them, 27 potentially synthetic lethal target genes were identified with the following properties: (i) unaffected genes by hemizygous/homozygous LOF mutations; (ii) prenatal lethality in knockout mice; and (iii) vulnerability of leukemia cells by CRISPR and shRNA knockout screens. In -7/del7q cells, we also identified 26 up or down-regulated genes mapping on other chromosomes as downstream pathways or compensation mechanisms. Our findings shed light on the pathogenesis of -7/del7q MNs, while 27 potential synthetic lethal target genes and 26 differential expressed genes allow for a therapeutic window of -7/del7q.

5G2 mutant mice model loss of a commonly deleted segment of chromosome 7q22 in myeloid malignancies

“…In addition, Mo7/del(7q) is highly enriched in myeloid malignancies that develop in patients with aplastic anemia or germline mutations in genes such as NF1, SAMD9/9L , and GATA2 or following treatment with radiation or alkylating agents [ 3 , 4 ]. In patients with Mo7/del(7q), the transformation from MDS to AML is characterized by recurring cooperating mutations in NRAS/KRAS, SETBP1, RUNX1 , and other genes [ 5 ]. The lack of accurate in vitro and in vivo models is a major barrier to understanding how Mo7/del(7q) contributes to leukemogenesis.…”