Recurrent genomic aberrations combined with deletions of various tumour suppressor genes may deregulate the G1/S transition in CD4+CD56+ haematodermic neoplasms and contribute to the aggressiveness of the disease

Abstract

neoplasms (HDN) constitute a rare disease characterized by aggressive clinical behaviour and a poor prognosis. Tumour cells from HDN are leukaemic counterparts of plasmacytoid dendritic cells (pDCs). Despite increased knowledge of the ontogenetic origin of these tumours, the genetic causes and oncogenic signalling events involved in malignant transformation are still unknown. To delineate novel candidate regions and disease-related genes, we studied nine typical CD4 þ CD56 þ HDN cases using genome-wide high-resolution array comparative genomic hybridization (CGH). Genomic imbalances, which were predominantly losses, were frequently detected. Gross genomic losses or gains involving an entire chromosome were observed in eight cases. The most frequent imbalances were deletions of chromosome 9, chromosome 13 and partial losses affecting 17p or 12p. Combinations of deletions of tumour suppressor genes (TSG), namely RB1, CDKN1B (p27), CDKN2A, (p16 ink4a , p14 arf ) or TP53 (p53), were observed in all cases. These results indicate that deletion events altering G1/S regulation are crucial for HDN oncogenesis. Furthermore, in addition to frequent sporadic gene losses, in one case we observed a 8q24 interstitial deletion that brought MYC closer to miR-30b/miR30d, which may be related to their deregulation. Taken together, these results indicate that in addition to frequent G1/S checkpoint alterations, various genetic events could contribute to the chemoresistance of the tumour.

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study

“…As for the therapy-related forms of BPDCN, all six affected patients received chemotherapy for the first neoplasm; the two patients with prostate cancer also received radiotherapy; the patient with a previous non-Hodgkin's lymphoma 4 years ago underwent a double autologous HSCT. The median time of latency between the first exposure to cytotoxic treatment for the primary neoplasm and the diagnosis of BPDCN was 5 years (range, [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15].…”

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

“…1 Tumor cells infiltrate skin, bone marrow, peripheral blood, and lymph nodes and show the characteristic immunophenotypic profile CD4 1 CD56 1 HLA-DR hi CD123 1 lineage (Lin) 2 , although atypical profiles are reported. 8,9 BPDCN presents heterogeneous genetic features characterized by chromosomal losses and deletions 10,11 and a mutational landscape that overlaps with other hematologic malignancies without evidence of unique, disease-specific, driver genetic lesions. [12][13][14] As in myeloid and lymphoid malignancies, mutations in key epigenetic modifierencoding genes, such as TET2, ASXL1, and EZH2, have been described in a proportion of BPDCN cases, thus supporting a role for deregulation of epigenetic signaling in disease pathogenesis.…”

“…16 Deletion of chromosome 5q, commonly seen in myelodysplastic syndrome (MDS) and AML, is frequent in BPDCN. 10,11 Deletion 5q (outside of the 5q2 syndrome) is associated with increased risk of leukemic transformation in MDS 17 and with very poor prognosis in AML. 18,19 This is attributed to haploinsufficiency for critical 5q gene(s), which in cooperation with additional signaling networks, drives malignant transformation and clonal evolution in these disorders.…”

Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study

“…11 We previously demonstrated its applicability to the analysis of various hematologic neoplasms, including chronic lymphocytic leukemia (CLL), DLBCL, mantle cell lymphoma (MCL), and CD4 ϩ CD56 ϩ hematodermic neoplasms. [12][13][14][15] We also assessed its prognostic relevance and its feasibility using formalin-fixed paraffin-embedded (FFPE) tissues in MCL. 13 Here, we assess the prognostic value of GCNA (TP53, CDKN2A, REL, BCL2, MYC, and RB1) detected by QMPSF in DLBCL, in a setting of clinical trials based on the use of R-CHOP or R-CHOPlike regimens.…”