Deregulated expression of NKL homeobox genes in T-cell lymphomas

Abstract

Recently, we have presented a scheme, termed “NKL-code”, which describes physiological expression patterns of NKL homeobox genes in early hematopoiesis and in lymphopoiesis including main stages of T-, B- and NK-cell development. Aberrant activity of these genes underlies the generation of hematological malignancies notably T-cell leukemia. Here, we searched for deregulated NKL homeobox genes in main entities of T-cell lymphomas comprising angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), adult T-cell leukemia/lymphoma (ATLL), hepatosplenic T-cell lymphoma (HSTL), NK/T-cell lymphoma (NKTL) and peripheral T-cell lymphoma (PTCL). Our data revealed altogether 19 aberrantly overexpressed genes in these types, demonstrating deregulated NKL homeobox genes involvement in T-cell lymphomas as well. For detailed analysis we focused on NKL homeobox gene MSX1 which is normally expressed in NK-cells. MSX1 was overexpressed in subsets of HSTL patients and HSTL-derived sister cell lines DERL-2 and DERL-7 which served as models to characterize mechanisms of deregulation. We performed karyotyping, genomic and expression profiling, and whole genome sequencing to reveal mutated and deregulated gene candidates, including the fusion gene CD53-PDGFRB. Subsequent knockdown experiments allowed the reconstruction of an aberrant network involved in MSX1 deregulation, including chromatin factors AUTS2 and mutated histone HIST1H3B(K27M). The gene encoding AUTS2 is located at chromosome 7q11 and may represent a basic target of the HSTL hallmark aberration i(7q). Taken together, our findings highlight an oncogenic role for deregulated NKL homeobox genes in T-cell lymphoma and identify MSX1 as a novel player in HSTL, implicated in aberrant NK- and T-cell differentiation.

The NKL-code for innate lymphoid cells reveals deregulated expression of NKL homeobox genes HHEX and HLX in anaplastic large cell lymphoma (ALCL)

“…RQ-PCR and Western blot analyses confirmed prominent HLX activity in ALCL cell lines ( Figure 3B, 3C), with DEL showing the highest level. Overexpression of HLX has been detected in subsets of ALCL patients [35], supporting the pathological relevance of its activation. Furthermore, as indicated by transcriptome data of normal immune cells, TH17 cells did not express HLX (Supplementary Figure 1F), underlining its aberrant activity in ALCL.…”

“…Collectively, HHEX was downregulated and impacted apoptosis and differentiation thus performing tumor suppressor gene activities both in ILC3 and ALCL ( Figure 6). However, in subsets of both, ALCL and T-ALL www.oncotarget.com HHEX operates as an oncogene [13,35]. Thus, HHEX is the second identified NKL homeobox gene after MSX1 representing a tumor suppressor as well as an oncogene [17,18].…”

“…ALCL patient samples have been shown to overexpress several NKL homeobox genes, indicating an oncogenic role for these genes in this malignancy [35]. However, ALCL cell lines DEL, SR-786, SU-DHL-1 and SUP-M2 expressed only low transcript levels of HHEX in comparison to controls (Figure 2A, 2B), discounting oncogenic activity for this ILC3-specific gene in these cells.…”

“…Real-time quantitative (RQ)-PCR analysis was performed with the 7500 Real-time System, using commercial buffer and primer sets (Thermo Fisher Scientific, Darmstadt, Germany). Quantification of MSX1 was performed as described previously [35]. For normalization of expression levels we analyzed the transcript of TATA box binding protein (TBP).…”

Deregulated NKL Homeobox Genes in B-Cell Lymphoma

“…Mechanisms of aberrant gene activation are presented by chromosomal rearrangements and deregulated activites of TFs, chromatin factors, and signalling pathways [18,24,27,30]. Furthermore, deregulated NKL homeobox genes play a significant role in T-cell lymphoma as well, underlining their oncogenic potential in T-cells [31].…”