Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies

Abstract

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

A new regulatory mechanism of protein phosphatase 2A activity via SET in acute myeloid leukemia

“…Moreover, we found that p38β binding stabilizes the SET protein in the cytoplasm, demonstrating a new role for p38β. We had previously demonstrated that SETBP1 binds to and stabilizes SET, facilitating PP2A inhibition 25 , and this result has been confirmed in other reports 46,47 . Here we further characterize this mechanism by showing that p38β co-localizes with SET, SETBP1, and PP2A, regulating PP2A activity in AML cells.…”

Somatic SETBP1 mutations in myeloid neoplasms

“…A most recent study has proposed very surprising but interesting concepts by comparing somatic and germline SETBP1 mutations [71]. They described that consequence of SETBP1 mutations are different among substitutions in SETBP1 residues.…”

“…On the other hand, substitutions in residue D868 led to the largest increase in protein levels. Cases with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations [71]. While these updated functional studies are helpful to understand biological mechanisms of leukemogenesis, therapeutic strategy to this distinct molecular target, SETBP1 mutation, is not established yet and requires further investigation.…”

De novo mutations in theSETnuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability

“…The gene was initially described as a translocation‐derived fusion gene in acute leukemia, where it has a proto‐oncogenic role (von Lindern et al., ). Strikingly, a dual role in cancer and ID/developmental disorders, respectively related to somatic and germline mutations, has been observed for numerous ID genes, such as SETBP1 , HRAS , EZH2 , SETBP1 , ARID1A , and ASXL1 and ASXL2 (Hoischen, Krumm, & Eichler, and references therein; Acuna‐Hidalgo et al., ; Ronan, Wu, & Crabtree, ).…”