The enigma of monosomy 7

Area of Science:

• Genetics and Genomics
• Oncology
• Molecular Biology

Background:

• Monosomy 7 (-7) and deletions of chromosome 7 (del(7q)) are frequent chromosomal aberrations in myeloid tumors.
• Previous attempts to identify recessive tumor-suppressor genes in del(7q) were unsuccessful.
• Current understanding suggests tumor suppressors on 7q act in a haploinsufficient manner.

Purpose of the Study:

• To identify and validate genes on chromosome 7q responsible for myeloid tumor development.
• To elucidate the roles of specific genes in myeloid tumorigenesis associated with -7/del(7q).

Main Methods:

• Utilized advanced technologies like microarray comparative genomic hybridization and high-throughput sequencing.
• Employed gene targeting in mouse models for validation of candidate genes.
• Analyzed gene mutations and their frequencies in myeloid tumors.

Main Results:

• Identified SAMD9 (sterile alpha motif domain 9) and SAMD9L (SAMD9-like) as genes whose mutations cause hereditary infantile myelodysplastic syndrome (MDS) with monosomy 7.
• Demonstrated that SAMD9/SAMD9L deficiency leads to MDS development in mice, suggesting their role in sporadic MDS with -7/del(7q).
• Found loss-of-function mutations in EZH2 (enhancer of zeste homolog 2) and MLL3 (mixed lineage leukemia 3) in some myeloid tumors, indicating their contribution to tumorigenesis, often cooperating with other genetic alterations.

Conclusions:

• SAMD9 and SAMD9L are crucial in the pathogenesis of MDS with monosomy 7.
• EZH2 and MLL3 mutations contribute to myeloid tumorigenesis, but their roles differ from SAMD9/SAMD9L, often requiring cooperation with other genetic events.
• The complex nature of myeloid tumors with -7/del(7q) arises from the distinct roles and significance of multiple lost or mutated genes.