The paradox of 20q11.21 amplification in a subset of cases of myeloid malignancy with chromosome 20 deletion

Abstract

Deletion of the long arm of one chromosome 20 (del(20q)) is a well-recognized abnormality in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and is presumed to cause loss of a tumor suppressor gene at 20q12. In a previously published series of MDS and AML cases, which had lost this region via unbalanced translocation, around 40% of cases were shown to have additional copies of the chromosome 20 abnormalities, with resulting gain or amplification of the retained parts of chromosome 20, most often 20q11.2. We have used FISH and array comparative genomic hybridization, to define further the retained and amplified regions. We now report targeted amplification of 20q11.21 in four of the 22 cases selected for further study and in one new case. The shortest amplified region of 250 kb in a series of five patients with three to ten copies of the 20q11.21 region contained the complete HCK, TM9SF4, PLAGL2, and POFUT1 genes. By RT-PCR we have shown that there is correlation between amplification and increased expression of these four genes in most cases. Localized and high level amplification of the common 250 kb region is evidence for activation of an oncogene in this region in these MDS and AML cases. Cases with 20q11.21 amplification tended to have a high proportion of erythroblasts in the marrow, with two cases diagnosed as erythroleukemia (AML-M6). Chromosome sub-band 20q11.21 amplification may therefore prove to be a marker of a specific subset of AML/MDS with a significant erythroid component.

Microarray CGH analysis of hematological patients with del(20q)

“…The precise localization of CDRs and CRRs showed some inconsistent results between several reports. The difference might be partly Additionally, the amplification of retained parts of the chromosome 20 had been reported [16] and 20q11.21 as a commonly gained region (CGR) (250kb) had been identified by Mackinnon et al [17] All patients with 20q11.21 amplification had a high proportion of erythroblast in the marrow (2 M6, 3 MDS with erythroid hyperplasia and morphology approaching erythroleukemia) and had an adverse prognosis. In our series, the results show similar to those of Mackinnon et al [17] 5 patients (cases 3,7,9,10,13) have the amplification of retained region of 20q, including 20q11.21 and 20q13.33.…”

Pleomorphic adenoma gene-like 2 regulates expression of the p53 family member, p73, and induces cell cycle block and apoptosis in human promonocytic U937 cells

“…Considering that over-expression of PLAGL2 has been linked to a subset of MDS cases [16], it is interesting to note that pro-apoptotic cytokines, including the p73 target TRAIL, are believed to contribute to the increased frequency of apoptosis in MDS marrow [44]. While DR3 is not a known p73 target gene, there was a greater increase in DR3 mRNA and protein relative to DR5, suggesting that this death receptor may also play a role in PLAGL2-induced apoptosis.…”

“…Given the implication of PLAGL2 in the pathogenesis of MDS and AML [14][15][16], understanding the mechanisms of PLAGL2 actions in human myeloid cells may provide insights into the potential role of PLAGL2 in these blood diseases. The present study shows that PLAGL2-induced cell cycle block and apoptosis in the human myelomonocytic U937 cell line is not via bNip-3 or SP-C pathways as demonstrated in mouse Balb/c3T3 fibroblasts, neuroblastoma Neuroa2a cells and mouse lung epithelium [10,11].…”

“…Although the mechanism of PLAGL2-induced lung oncogenesis is not completely understood, PLAGL2 transgenic mice did show an increase in epithelial cells expressing SP-C, suggesting a role for PLAGL2 in the expansion of SP-C expressing cells. PLAGL2 was also identified as a cooperating oncogene in an inv(16) AML mouse model and was shown to be preferentially increased in human inv (16) AML samples [14]. Subsequently, it was demonstrated that PLAGL2 upregulated the thrombopoietin receptor Mpl in inv (16) AML mice, however, there was no correlation between PLAGL2 and Mpl expression in gene expression data sets of human AML [15].…”

“…Amplification of 20q11.21 was also observed in a number of human myelodysplastic syndrome (MDS) cases [16]. MDS is comprised of a heterogeneous group of clonal disorders characterized by inefficient hematopoiesis, and is considered a pre-leukemic condition, which can progress to AML [17].…”