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.