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The enigma of monosomy 7

Toshiya Inaba, Hiroaki Honda and Hirotaka Matsui

Abstract

Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (-7) and interstitial deletions of chromosome 7 [del(7q)] have been established as one of the most frequent chromosomal aberrations found in essentially all types of myeloid tumors regardless of patient age and disease etiology. In the last century, researchers sought recessive myeloid tumor-suppressor genes by attempting to determine commonly-deleted regions (CDRs) in del(7q) patients. However, these efforts were not successful. Today, tumor-suppressors located in 7q are believed to act in a haplo-insufficient fashion, and powerful new technologies such as microarray comparative genomic hybridization and high-throughput sequencing allow comprehensive searches throughout the genes encoded on 7q. Among those proposed as promising candidates, four have been validated by gene-targeting in mouse models. SAMD9 and SAMD9L encode related endosomal proteins, mutations of which cause hereditary diseases with strong propensity to infantile MDS harboring monosomy 7. Because MDS develops in SAMD9L-deficient mice over their lifetime, SAMD9/SAMD9L are likely responsible for sporadic MDS with -7/del(7q) as the sole anomaly. EZH2 and MLL3 encode histone-modifying enzymes; loss of function mutations of these are detected in some myeloid tumors at high frequencies. In contrast to SAMD9/SAMD9L, loss of EZH2 or MLL3 likely contributes to myeloid tumorigenesis in cooperation with additional specific gene alterations such as of TET2 or genes involved in the p53/Ras pathway, respectively. Distinctive roles with different significance of the loss of multiple responsible genes render the complex nature of myeloid tumors carrying -7/del(7q).

  • Submitted December 22, 2017.
  • Accepted March 29, 2018.