TY - JOUR
T1 - Genomics of deletion 7 and 7q in myeloid neoplasm
T2 - from pathogenic culprits to potential synthetic lethal therapeutic targets
AU - Mori, Minako
AU - Kubota, Yasuo
AU - Durmaz, Arda
AU - Gurnari, Carmelo
AU - Goodings, Charnise
AU - Adema, Vera
AU - Ponvilawan, Ben
AU - Bahaj, Waled S.
AU - Kewan, Tariq
AU - LaFramboise, Thomas
AU - Meggendorfer, Manja
AU - Haferlach, Claudia
AU - Barnard, John
AU - Wlodarski, Marcin
AU - Visconte, Valeria
AU - Haferlach, Torsten
AU - Maciejewski, Jaroslaw P.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/10
Y1 - 2023/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85168981622&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85168981622&partnerID=8YFLogxK
U2 - 10.1038/s41375-023-02003-x
DO - 10.1038/s41375-023-02003-x
M3 - Article
C2 - 37634012
AN - SCOPUS:85168981622
SN - 0887-6924
VL - 37
SP - 2082
EP - 2093
JO - Leukemia
JF - Leukemia
IS - 10
ER -