Role of Genetic Evolution and Germline Mutations in SAMD9 and SAMD9L Genes

Acquired deletions on chromosome 7 (monosomy 7/del7q) are common in myeloid neoplasms, especially pediatric MDS and AML. Although these tumors have historically been reported to occur within families, suggesting a genetic predisposition, the genetic lesion(s) that initiate these diseases has remained elusive until the last few years. Following a series of publications in which germline mutations in SAMD9 and SAMD9L were reported in a MIRAGE syndrome and Ataxia Pancytopenia syndrome, respectively, our group and others described similar heterozygous missense germline mutations in pediatric MDS, especially non-syndromic familial MDS with monosomy 7. Mutations in SAMD9 and SAMD9L have now also been reported in transient monosomy 7, inherited bone marrow failure and AML. Collectively, it is estimated that germline mutations in these genes are present in nearly 20% of children with MDS, with a strong enrichment in those with monosomy 7. Surprisingly, SAMD9 and SAMD9L are paralogous genes adjacently located on human chromosome 7 at band 7q21, and the monosomy 7 clone that expands in children universally lacks the pathologic germline variant. Expression of the mutant proteins in cells results in profound growth suppression, suggesting that there is strong selective pressure for hematopoietic cells to not express the mutant alleles. In addition to chromosome loss, additional methods that suppress expression of the pathologic allele have been described. These include copy neutral loss of heterozygosity (CN-LOH) with duplication of the wild-type allele or the somatic acquisition of additional mutations in cis with the germline mutation that counteract the growth suppressive effect of the germline mutation. The clinical phenotype is largely dictated by the revertant mutation in the dominant hematopoietic clone within the patient's bone marrow. Those with an expansion of a CN-LOH clone are more commonly asymptomatic, in contrast to those patients with a dominant monosomy 7 clone. Progression to higher grade MDS or AML is associated with the acquisition of additional somatic mutations including mutations in SETBP1, KRAS and RUNX1. The recognition of these germline mutations has had an immediate impact on the clinical management of children with MDS, including their family members, and ongoing clinical work in the pediatric MDS community is aimed at establishing guidelines for the pathologic diagnosis, clinical monitoring and treatment for these patients. In addition to these ongoing clinical pursuits, there is significant research interest in these genes, the function of their proteins in hematopoietic cells and how the germline mutations alter the function of the wild-type protein. The SAMD9 and SAMD9L proteins are largely uncharacterized and have been shown to be important in endocytosis, growth factor signaling and to have antiviral properties. Intriguingly, SAMD9 and SAMD9L are both induced by inflammatory signals, including interferons, suggesting a link between inflammatory stress and the disease phenotype. Ongoing studies are aimed at developing models, including in vitro and in vivo models, to understand the mechanisms by which these germline mutations can ultimately lead to the development of pediatric MDS and related disorders.