Transformation of normal human cells in the absence of telomerase activation

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A t(4;13)(q21;q14) translocation in B-cell chronic lymphocytic leukemia causing concomitant homozygous DLEU2/miR15a/miR16-1 and heterozygous ARHGAP24 deletions

13q14 deletion is the most recurrent chromosomal aberration reported in B-CLL, having a favorable prognostic significance when occurring as the sole cytogenetic alteration. However, its clinical outcome is also related to the deletion size and number of cells with the del(13)(q14) deletion. In 10% of cases, 13q14 deletion arises following a translocation event with multiple partner chromosomes, whose oncogenic impact has not been investigated so far due to the assumption of a possible role as a passenger mutation. Here, we describe a t(4;13)(q21;q14) translocation occurring in a B-CLL case from the diagnosis to spontaneous regression. FISH and SNP-array analyses revealed a heterozygous deletion at 4q21, leading to the loss of the Rho GTPase Activating Protein 24 (ARHGAP24) tumor suppressor gene, down-regulated in the patient RNA, in addition to the homozygous deletion at 13q14 involving DLEU2/miR15a/miR16–1 genes. Interestingly, targeted Next Generation Sequencing analysis of 54 genes related to B-CLL indicated no additional somatic mutation in the patient, underlining the relevance of this t(4;13)(q21;q14) aberration in the leukemogenic process. In all tested RNA samples, RT-qPCR experiments assessed the downregulation of the PCNA, MKI67, and TOP2A proliferation factor genes, and the BCL2 anti-apoptotic gene as well as the up-regulation of TP53 and CDKN1A tumor suppressors, indicating a low proliferation potential of the cells harboring the aberration. In addition, RNA-seq analyses identified four chimeric transcripts (ATG4B::PTMA, OAZ1::PTMA, ZFP36::PTMA, and PIM3::BRD1), two of which (ATG4B::PTMA and ZFP36::PTMA) failed to be detected at the remission, suggesting a possible transcriptional remodeling during the disease course. Overall, our results indicate a favorable prognostic impact of the described chromosomal aberration, as it arises a permissive molecular landscape to the spontaneous B-CLL regression in the patient, highlighting ARHGAP24 as a potentially relevant concurrent alteration to the 13q14 deletion in delineating B-CLL disease evolution

Rare recurrent t(15;21) translocations disrupting RUNX1 in myeloid leukemia.

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A rare but recurrent t(8;13)(q24;q14) translocation in B-cell chronic lymphocytic leukaemia causing MYC up-regulation and concomitant loss of PVT1, miR-15/16 and DLEU7

B-cell chronic lymphocytic leukaemia (B-CLL) is the most common haematological malignancy in Western countries. Trisomy 12 (12%), and deletions of 13q14 (50%), 11q23 (18%) and 17p13 (7%) are the most frequent chromosomal aberrations (Palamarchuk et al, 2010). 13q14 losses, associated with better prognosis, are primary changes resulting in loss of MIR15A/MIR16-1 and DLEU7 (Palamarchuk et al, 2010). Notably, the 10% of these deletions occur together with unbalanced translocations with multiple partners (Puiggros et al, 2014). Two cases with t(8;13)(q14;q24) translocations have been described, although not characterized at molecular level (Gardiner et al, 1997; Put et al, 2012). 8q24 rearrangements are generally rare in CLL and their prognostic significance is unclear.This work was supported by the AIRC (Associazione Italiana per la Ricerca sul Cancro).Peer Reviewe

t(15;21) translocations leading to the concurrent downregulation of RUNX1 and its transcription factor partner genes SIN3A and TCF12 in myeloid disorders

Through a combined approach integrating RNA-Seq, SNP-array, FISH and PCR techniques, we identified two novel t(15;21) translocations leading to the inactivation of RUNX1 and its partners SIN3A and TCF12. One is a complex t(15;21)(q24;q22), with both breakpoints mapped at the nucleotide level, joining RUNX1 to SIN3A and UBL7-AS1 in a patient with myelodysplasia. The other is a recurrent t(15;21)(q21;q22), juxtaposing RUNX1 and TCF12, with an opposite transcriptional orientation, in three myeloid leukemia cases. Since our transcriptome analysis indicated a significant number of differentially expressed genes associated with both translocations, we speculate an important pathogenetic role for these alterations involving RUNX1.status: publishe

1q23.1 homozygous deletion and downregulation of Fc receptor-like family genes confer poor prognosis in chronic lymphocytic leukemia

The identification of chromosome 1 translocations and deletions is a rare and poorly investigated event in chronic lymphocytic leukemia (CLL). Nevertheless, the identification of novel additional molecular alterations is of great interest, opening to new prognostic and therapeutic strategies for such heterogeneous hematological disease. We here describe a patient affected by CLL with a mutated IGHV status, showing a balanced t(1;3)(q23.1;q21.3) translocation and a der(18)t(1;18)(q24.2;p11.32), accompanying the recurrent 13q14 heterozygous deletion in all analyzed cells at onset. By combining whole-genome sequencing, SNP array, RNA sequencing, and FISH analyses, we defined a 1q23.1 biallelic minimally deleted region flanking translocations breakpoints at both derivative chromosome 1 homologues. The deletion resulted in the downregulation of the Fc receptor-like family genes FCRL1, FCRL2, and FCRL3 and in the lack of expression of FCRL5, observed by RT-qPCR. The mutational status of TP53, NOTCH1, SF3B1, MYD88, FBXW7, and XPO1 was investigated by targeted next-generation sequencing, detecting a frameshift deletion within NOTCH1 (c.7544_7545delCT). We hypothesize a loss of tumor suppressor function for FCRL genes, cooperating with NOTCH1 mutation and 13q14 genomic loss in our patient, both conferring a negative prognosis, independently from the known biological prognostic factors of CLL.This work was supported by the AIRC (Associazione Italiana per la Ricerca sul Cancro; AIRC IG No. 15413 for CTS)

FOXP1 and TP63 involvement in the progression of myelodysplastic syndrome with 5q- and additional cytogenetic abnormalities

The progression of low-risk del(5q) myelodysplastic syndrome to acute myeloid leukemia is increased when associated with mutations of TP53, or with additional chromosomal abnormalities. However, to date the prognostic impact and molecular consequences of these rearrangements were poorly investigated. Single additional alterations to del(5q) by balanced chromosome rearrangements were rarely found in myelodysplasia. In particular, balanced alterations involving TP63 and FOXP1 genes were never reported in the literature