We'll Get Practice Pronouncing Schinzel Giedion: Somatic SET BP1 Mutations in Myeloid Neoplasms

Sakaguchi H, Okuno Y, Muramatsu H, et al. Exome sequencing identifies secondary mutations of SET BP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet. 2013;45:937-941.

Phenotypes associated with acquired mutations often mimic those linked to congenital mutations of the same gene, but sometimes the consequences of the two types of mutations are distinct. For instance, although both congenital and acquired mutations in ATRX result in alpha thalassemia (ATRX congenital mutations also cause mental retardation and dysmorphology), and both congenital and acquired mutations of TP53 are linked to the development of common epithelial tumors, germline mutations in FANCD1/BRCA2 cause Fanconi anemia, while somatic FANCD1/BRCA2 mutations are associated with breast, ovarian, prostate, and other epithelial cancers. Discovery of acquired tumorassociatedmutations in a gene where germline mutations are known but result in something quite different can be surprising and often raises new questions about cancer pathobiology.

Such is the case with SETBP1, which encodes SET binding protein 1 and is mutated congenitally in a devastating but rare autosomal recessive neurodegenerativedysmorphology syndrome called Schinzel–Giedion midface retraction syndrome (SGS). Unexpectedly, during whole-exome sequencing analysis of myeloid neoplasms, SETBP1 was found to be mutated somatically in 10 percent of patients with unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN), 4 percent with chronic myelomonocytic leukemia (CMML), and 24 percent with atypical chronic myeloid leukemia (aCML).¹  Children with SGS have a high incidence of neuroepithelial tumors, but they are not clearly predisposed to myeloid neoplasms. Investigators in the Maciejewski lab at Cleveland Clinic and the Ogawa lab in Japan have now extended the SETBP1 observations in other myeloid disorders.

The key findings from the new studies are that SETBP1 mutations are present in 17 percent of secondary AML (sAML) and 15 percent of CMML cases in the Makishima series and in 7.6 percent of patients with the pediatric MDS/MPN juvenile myelomonocytic leukemia (JMML) in the Sakaguchi cohort. Five other groups in the United States and Europe have presented data about recurrent SETBP1 mutations in their patients with MDS (2.2-4.3% mutation incidence), primary myelofibrosis and other MPNs (2.5-4%), MDS/MPN overlap syndromes including CMML (6.2-9.4%), and sAML (1.7%).^2-6  Mutations in SETBP1 in these series have been associated with disease progression, higher white counts, higher-risk karyotypes such as monosomy 7, and poorer clinical outcomes.

What does the SETBP1 protein do? Its precise function in both health and disease is incompletely characterized, but it is known to bind to the SET nuclear oncoprotein (named after a transcript found in 1992 in a Dutch leukemia patient with the initials S.E.), resulting in inhibition of the putative tumor suppressor protein phosphatase type 2a (PP2A). Identified mutations in both SGS and myeloid neoplasia cluster in the SKI homologous region of SETBP1; SKI (SKI = Sloan-Kettering Institute, the place of discovery) is a proto-oncogene that encodes a component of the histone deacetylase complex, and this may give insight into the epigenetic and transcriptional consequences of SETBP1 mutation. Makishima and colleagues showed that mutations in SETBP1 are gain-of-function and are associated with diminished PP2A activity. Additionally, the investigators showed direct transcriptional activation of the HOXA9 and HOXA10 genes by SETBP1 in both human and mouse myeloid progenitors, and expression of mutant Setbp1 immortalized murine progenitor cells in a Hox9a/10a-dependent manner.