Simultaneous Translocation of Both TCR Loci (14q11) with Rare Partner Loci (Xq22 and 12p13) in a Case of T-lymphoblastic Leukemia

Abstract

The most common recurrent cytogenetic abnormalities in T-lymphoblastic leukemia (T-acute lymphoblastic leukemia [T-ALL]) involve T-cell receptor (TCR) loci and a variety of partner genes, including HOX11, HOX11L2, MYC, and TAL1. In this report, we present a rare case involving simultaneous translocation of the TCR α/δ loci with different partner loci (Xq22 and 12p13); this resulted in a poor prognosis. Chromosomal analysis showed 46,Y,t(X;14)(q22;q11.2),t(12;14)(p13;q11.2) and FISH analysis by using a T-cell receptor alpha delta DNA probe, Split Signal (DakoCytomation, Denmark), showed translocations at the same TCR α/δ locus on both chromosomes. FISH with 2 bacterial artificial chromosome clones showed break apart signal, which suggests involvement of the IRS4 gene. To our knowledge, this is the first report of T-ALL in which both TCR α/δ loci were translocated with different partner loci, and 1 of the partner loci, Xq22, was a rare translocation partner locus that included IRS4 gene.

IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation

“…In fact, the inference that IRS4 is a constitutive active IRS is also in line with our finding that the Irs4 gene is a target for retroviral insertional mutagenesis, as this process leads with few exceptions to transcriptional deregulation of the target genes rather than to mutations affecting protein function34. The notion that IRS4 is a constitutive active oncogenic protein primarily regulated transcriptionally also explains the recent observations that chromosomal translocation events can activate Irs4 expression, leading to T-cell acute lymphoblastic leukaemia3536 and subungual exostosis (a benign bone and cartilage producing tumour)37. In addition, in human hepatocellular carcinomas (HCC), IRS4 expression is frequently upregulated compared with hepatocytes38, and its role in this malignancy has been further substantiated in the HEPG2 hepatoblastoma cell line where IRS4 plays an important role in cell proliferation39.…”

The Genetics and Mechanisms of T-Cell Acute Lymphoblastic Leukemia

“…In addition, activating mutations in the PI3K-AKT pathway that are detected at a lower frequency in T-ALL are found in AKT1, PI3K catalytic and regulatory subunit genes, PIKC3A, and PIK3CD (Gutierrez et al 2009;Zuurbier et al 2012;Liu et al 2017). Moreover, the t(X;7)(q22;q34) and t(X;14)(q22;q11.2) translocations induce overexpression of IRS4 (Karrman et al 2009b;Kang et al 2012), a signaling factor that activates AKT (Uchida et al 2000). Importantly, inhibition of the PI3K/AKT/mTOR axis induces apoptosis and suppresses the growth of T-ALL in mouse models, cell lines and primary human T-ALL xenografts (Evangelisti et al 2011;Subramaniam et al 2012;Piovan et al 2013;Dail et al 2014) thus representing a potential therapeutic opportunity for T-ALL patients.…”

Pathogenetic Dichotomy in Angioleiomyoma

“…In T-ALL, t(X;7)(q22;q34) brought IRS4 under the transcriptional control of T-cell receptor beta locus (from 7q34) regulatory elements (48). Rearrangements of Xq22/IRS4 and 14q11.2/Tcell receptor alpha-delta locus (TCRAD) were also found in a T-ALL carrying the translocation t(X;14)(q22;q11.2) (49). In a pan-cancer study, IRS4 was overexpressed in 10 different tumor types due to regulatory elements, such as enhancers being rearranged and juxtaposed near to IRS4 (50,51).…”