Retroviral insertional mutagenesis identifies the del(5q) genes, CXXC5, TIFAB and ETF1, as well as the Wnt pathway, as potential targets in del(5q) myeloid neoplasms

Abstract

Retroviral insertional mutagenesis identifies the del(5q) genes, CXXC5, TIFAB and ETF1, as well as the Wnt pathway, as potential targets in del(5q) myeloid neoplasmsAn interstitial deletion of the long arm of chromosome 5, del(5q), is a recurring abnormality in myeloid disorders, including myelodysplastic syndromes (MDS), de novo acute myeloid leukemia (AML), and therapy-related myeloid neoplasms (t-MN) comprising therapy-related MDS and AML (t-MDS/t-AML).1 In t-MN, a del(5q) occurs in approximately 40% of patients and is associated with prior therapy with alkylating agents, a complex karyotype, TP53 mutations, a strong propensity to progress to t-AML, and a poor outcome.2,3 We previously identified two haploinsufficient tumor suppressor genes on 5q, the early growth response gene, EGR1 [(5q31.2, deleted in all t-MN with a del(5q)] and the adenomatous polyposis coli gene, APC [5q22.2, deleted in >95% of tMNs with a del(5q)], and showed that heterozygous loss of Egr1 and Apc in mice promote the pathogenesis of MDS/AML, in co-operation with knockdown of Trp53 and/or alkylating agent therapy.4 EGR1 is a member of the WT-1 family of transcription factors and is a transcriptional regulator of many tumor suppressor genes, including TP53, CDKN1A/p21 and TGFB.5 The APC protein acts as a tumor suppressor and is a negative regulator of the WNT signaling pathway.6 Adding to the difficulty

Epistasis between TIFAB and miR-146a: neighboring genes in del(5q) myelodysplastic syndrome

“…TIFAB is a gene that is deleted in nearly all reported cases of del(5q) MDS and acute myeloid leukemia (AML). 2,3 As expected, TIFAB expression is significantly lower in CD34 + and BM mononuclear (MNC) cells isolated from MDS patients with del(5q) as compared with cells from MDS patients diploid at chr 5q. Recently we have shown that hematopoieticspecific deletion of Tifab results in progressive BM and blood defects, including aberrant HSPC proportions, altered myeloid differentiation and progressive cytopenia.…”

“…2 In a separate study, TIFAB was identified by a retroviral insertional mutagenesis screen as a target in del(5q) myeloid neoplasms. 3 …”

Computational analysis and verification of molecular genetic targets for glioblastoma

“…Further verification found that ETF1 could be involved in the development of breast cancer and might serve as a biomarker of the HER2 subtype group [26]. Stoddart et al found that ETF1 could produce potential oncogenic abnormal proteins and may be a potential therapeutic target for myeloid tumors [27]. In addition, Yang et al investigated the mechanism of treating diabetes mellitus and nephropathy with mesenchymal stem cells with bioinformatics analysis, and further identified ETF1 playing a vital role in the process as a DEG [28].…”

Chronic immune response dysregulation in MDS pathogenesis

“…In an independent study, TIFAB was identified by a retroviral insertional mutagenesis screen as a target in del(5q) myeloid neoplasms. 21 Tifab-deficient mice develop mild hematopoietic defects and occasionally BM failure. 11 However, hematopoietic-specific deletion of Tifab and miR-146a together results in a highly penetrant BM failure, which better recapitulates human del(5q) MDS.…”