Sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines

Abstract

BackgroundHodgkin lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL), are forms of malignant lymphoma defined by unique morphologic, immunophenotypic, genotypic, and clinical characteristics, but both overexpress CD30. We used sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization to screen HL-derived cell lines (KMH2 and L428) and ALCL cell lines (DEL and SR-786) in order to identify disease-associated gene copy number gains and losses.ResultsSignificant copy number gains and losses were observed on several chromosomes in all four cell lines. Assessment of copy number alterations with 26,819 DNA segments identified an average of 20 genetic alterations. Of the recurrent minimally altered regions identified, 11 (55%) were within previously published regions of chromosomal alterations in HL and ALCL cell lines while 9 (45%) were novel alterations not previously reported. HL cell lines L428 and KMH2 shared gains in chromosome cytobands 2q23.1-q24.2, 7q32.2-q36.3, 9p21.3-p13.3, 12q13.13-q14.1, and losses in 13q12.13-q12.3, and 18q21.32-q23. ALCL cell lines SR-786 and DEL, showed gains in cytobands 5p15.32-p14.3, 20p12.3-q13.11, and 20q13.2-q13.32. Both pairs of HL and ALCL cell lines showed losses in 18q21.32-18q23.ConclusionThis study is considered to be the first one describing HL and ALCL cell line genomes at sub-megabase resolution. This high-resolution analysis allowed us to propose novel candidate target genes that could potentially contribute to the pathogenesis of HL and ALCL. FISH was used to confirm the amplification of all three isoforms of the trypsin gene (PRSS1/PRSS2/PRSS3) in KMH2 and L428 (HL) and DEL (ALCL) cell lines. These are novel findings that have not been previously reported in the lymphoma literature, and opens up an entirely new area of research that has not been previously associated with lymphoma biology. The findings raise interesting possibilities about the role of signaling pathways triggered by membrane associated serine proteases in HL and aggressive NHL, similar to those described in epithelial tumors.

FOXO1 is a tumor suppressor in classical Hodgkin lymphoma

“…15 The data of miRNA arrays, showing high expression of miR-182 and miR-183 in L428 and L1236 cell lines, 44 and high expression of miR-96 in HRS cells of EBV-negative nodular sclerosis cHL cases are also in agreement with our results. 44 Our data on FOXO1 copy number loss in cHL cell lines are in accordance with the previously described 13q13.1-q21.32 loss in L428 and KM-H2 cell lines 33 and the 13q loss in L1236 cells. 45 In SUP-HD1, we found a derivative chromosome 13 with interstitial deletion similar to previous observations.…”

“…23,33,34 To specifically investigate copy number changes of the FOXO1 locus, we performed FISH on the cHL cell lines KM-H2, L428, L1236, SUP-HD1, and U-HO1. We identified an interstitial deletion of chromosome 13q involving FOXO1 in the diploid cell line SUP-HD1, whereas in the triploid cell lines KM-H2 and L1236, as well as in tetraploid L428, only 2 chromosomes 13 (harboring the FOXO1 locus) were present (supplemental Figure 3).…”

GSK3-SCFFBXW7 targets JunB for degradation in G2 to preserve chromatid cohesion before anaphase

“…In fact, ALCLs are characterized by a complex karyotype, different numerical and structural chromosomal abnormalities and chromosomal imbalances. [4][5][6][7][8][9] The JunB transcription factor has been shown to contribute to the pathogenesis of ALK-positive ALCLs 10 where its abnormally high accumulation is explained by at least two mechanisms: (i) increased JUNB transcription dependent on Erk1/2 kinase activation by NPM-ALK and (ii) increased JUNB translation mediated by mTOR activation by AKT, which is induced by NPM-ALK via activation of PI3K. However, how JunB promotes ALCL lymphomagenesis is still unclear.…”

The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin–proteasome system

“…It is ubiquitously expressed in normal human tissues and regulates gene transcription, cell cycle control and apoptosis (Nagashima et al, 2003). Distorted ING3 expression has been found in human head and neck squamous cell carcinomas (HNSCCs) and several lymphoma-derived cell lines (Gunduz et al, 2002(Gunduz et al, , 2008Fadlelmola et al, 2008). In melanoma cells, we have shown that ING3 promotes ultraviolet (UV)-induced apoptosis through the Fas/caspase-8-dependent pathway (Wang and Li, 2006).…”