Clonal expansion of p53 mutant cells is associated with brain tumour progression

Nature ◽  
1992 ◽  
Vol 355 (6363) ◽  
pp. 846-847 ◽  
Author(s):  
David Sidransky ◽  
Tom Mikkelsen ◽  
Karl Schwechheimer ◽  
Mark L. Rosenblum ◽  
Web Cavanee ◽  
...  
2011 ◽  
Vol 223 (06) ◽  
Author(s):  
J Bode ◽  
A Sabag ◽  
S Kietz ◽  
G Neufeld ◽  
M Lakomek

2021 ◽  
Vol 108 (Supplement_2) ◽  
Author(s):  
A Vassiliou ◽  
K Alavian ◽  
M Tsujishita ◽  
H Bae

Abstract Introduction Primary brain tumours originate from cells within the brain. The commonest malignant types are gliomas which are graded from I-IV. Emerging evidence has elucidated the function of the mitochondrially localised B-cell lymphoma-extra-large (Bcl-xL) protein, and its promotion of tumour progression-associated properties. Our lab has previously established that Bcl-xL-overexpressing neurons increase metabolic efficiency by producing more adenosine triphosphate and consuming less oxygen, which we assumed, fuels cancer cells to proliferate. Method We quantified the subcellular expression patterns of Bcl-xL in primary brain tumour samples through immunohistochemistry on a brain tissue microarray containing 16 glioma cases from Grades II-IV. We used antibodies against Bcl-xL, heat shock protein 60 for mitochondrial detection and proliferating cell nuclear antigen for cancerous cell detection. Results Bcl-xL is overexpressed in cancerous cells of Grade IV gliomas and is significantly greater than cancerous cells of Grade III and Grade II gliomas. Cancerous cells express higher levels of Bcl-xL than non-cancerous cells in all grades of glioma. Conclusions Bcl-xL-overexpressing neurons exhibit enhanced metabolic efficiency, contributing to increased proliferation rates. Future research should focus on the characterisation of ATP levels and oxygen consumption in glioma cells. Conclusively, pharmacological inhibition of Bcl-xL will suppress the proliferation rate in gliomas and cease cancer cell growth.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3533-3533 ◽  
Author(s):  
Norimitsu Inoue ◽  
Tomohisa Izui ◽  
Yoshiko Murakmai ◽  
Yuichi Endo ◽  
Jun-ichi Nishimura ◽  
...  

Abstract In PNH, a somatic mutation of PIGA in hematopoietic stem cells causes the deficiency of glycosylphosphatidylinositol-anchored proteins (GPI-AP), but the basis of clonal expansion of the PIGA-mutant cells is speculative. Because some patients with aplastic anemia develop PNH, GPI-AP deficient stem cells may have a survival advantage in the setting of immune-mediated bone marrow injury. However, in many patients with aplastic anemia, the GPI-AP deficient cell populations remain small or disappear. Therefore, we hypothesized that additional abnormalities in the PIGA-mutant stem cells account for clonal expansion. We previously reported a patient with PNH/aplastic anemia (J20) whose PIGA-mutant hematopoietic cells had a coexistent cytogenetic abnormality [46,XX,ins(12;12)(q14;q12q14)]. In this patient, the insertion disrupted the 3′ untranslated region of HMGA2, an architectural transcription factor whose aberrant expression causes benign mesenchymal tumors. Truncated HMGA2 transcripts lacking the acidic tail (the pathophysiologically relevant form) were identified in the double mutant cells. In the present study, we characterized a similar genetic abnormality in a patient with classical PNH. In this case, PIGA-mutant cells again had a concurrent der(12) [46,XX,ins(12)(p13q14q13)]. A 20 Mbp fragment from 12q13 to q14 and a 300bp fragment from 12q14 together containing exons 1–4 and part of exon 5 of HMGA2 were inserted inversely and directly, respectively, into intron 1 of TEL at 12p13. One of the breakpoints in the HMGA2 locus was at almost the same position as the HMGA2 breakpoint in patient J20. Truncated HMGA2 transcripts (lacking the acidic tail) were highly expressed in bone marrow cells. Full-length transcripts of TEL without any fusion partners were normally expressed and no other transcription units were disrupted by the breakpoints. That similar cytogenetic abnormalities were observed in these two patients suggests that aberrant expression of HMGA2, in concert with mutant PIGA, accounted for the clonal expansion and explains the benign tumor characteristics of PNH.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 173-173
Author(s):  
Ayala Tovy ◽  
Hyun Jung Park ◽  
Jaime M. Reyes ◽  
Anna Guzman ◽  
Rachel E. Rau ◽  
...  

Abstract The DNA Methyltransferase 3A (DNMT3A) gene is recurrently mutated in a large spectrum of hematologic malignancies, including acute myeloid leukemia (AML). About 25% of adult AML patients carry mutations in DNMT3A and these mutations are generally associated with poor prognosis. DNMT3A mutations have been also associated with aged-related clonal hematopoiesis of indeterminate potential (CHIP). The high prevalence of DNMT3A somatic mutations in AML and CHIP implies that cells with mutated DNMT3A have a competitive advantage over wild-type (WT) cells, resulting in clonal expansion. However, the downstream molecular mechanisms that underlie this phenotype are not clear. Tatton-Brown-Raman syndrome (TBRS) is a rare genetic disorder caused by heterozygous germline mutations in DNMT3A, characterized by overgrowth and developmental delay. In one particular family, a group of 4 children out of 12 were diagnosed with TBRS and were found to be heterozygous carriers of DNMT3A-R771Q mutation (DNMT3AR771Q) inherited from their mosaic father. Thus, this individual provides a unique opportunity to study the long-term consequences of DNMT3A mutations, as he harbors both WT and mutant cells. From this mosaic individual, we generated lymphoblastoid cell lines (LCLs) from the peripheral blood (PB) and measured DNMT3AR771Q variant allele frequency (VAF) in the LCL pool as well as in PB, saliva and urine, all collected at the same time. Strikingly, DNMT3AR771Q VAF in the LCL pool and in PB was substantially higher than in saliva and urine (respectively 30%, 45%, 10%, 4%), implying that levels of DNMT3A mosaicism are tissue-specific and that cells with mutated DNMT3A tend to expand in the blood but not in epithelia (figure 1A and figure1B). One hypothesis for the prevalence of DNMT3A mutations in AML is that its loss reduces the effectiveness of DNA repair leading to increased mutational rates. In order to test this, we compared the mutational loads in individual LCL clones that were WT or DNMT3A mutant using whole genome sequencing. Surprisingly, no clear differences were observed between WT and DNMT3AR771Q mutant cells, indicating that clonal expansion is unlikely to be secondary to a general increase in mutational burden. To explore the impact of DNMT3AR771Q mutation on DNA methylation, we performed whole-genome bisulfite sequencing (WGBS) on two WT and two DNMT3AR771Q LCL clones. We identified ~31,500 differentially methylated regions (DMRs) between WT and mutant clones, with the majority of DMRs being hypomethylated. Hypomethylated DMRs were associated with gene regulatory regions, mainly promoters and enhancer regions. These data suggest that the DNMT3AR771Q mutation affects DNA methylation setting at genomic regions that can directly affect transcription. Canyons are large genomic regions of low methylation that often occur around master regulators such as homeobox-containing genes. We previously showed in mice that DNMT3A regulates DNA methylation at canyon edges, with loss of DNMT3A resulting in canyon expansion. In agreement, DNMT3AR771Q mutant clones displayed larger canyons, particularly at loci marked by H3K27Ac and H3K4me3 (figure 1C). Gene Ontology analysis of genes falling into expanded canyons showed a significant enrichment for leukemia and stem cell-related genes, including members of the HOX family. RNAseq analysis of DNMT3AR771Q mutant LCL clones confirmed the upregulation of key cancer-associated genes. These data suggest that DNMT3A mutations may promote clonal expansion through hypomethylation and overexpression of stem cell and cancer-related genes In conclusion, by comparing WT and DNMT3Amutant LCL clones generated from the same individual, we show that DNMT3A mutations lead to significant hypomethylation and overexpression of key cancer-associated genes. Further studies on specific target genes will reveal critical pathways responsible for the clonal expansion of cells with mutated DNMT3A, paving the way for the development of new therapeutic strategies for malignancies with mutated DNMT3A. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4242-4242
Author(s):  
Yoshiko Murakami ◽  
Norimitsu Inoue ◽  
Tsutomu Shichishima ◽  
Hideyoshi Noji ◽  
Jun-Ichi Nishimura ◽  
...  

Abstract Abstract 4242 Paroxysmal nocturnal hemoglobinuria (PNH) is caused by a somatic mutation of PIG-A gene in one or few hematopoietic stem cells and subsequent clonal expansion of mutant stem cells. It is known that PIG-A mutation is insufficient to account for the clonal expansion required for clinical manifestation of PNH. We proposed a 3-step model of PNH pathogenesis. Step 1 involves the generation of a GPI-deficient hematopoietic stem cell by somatic mutation of PIG-A gene. Step 2 involves the immunological selection of GPI-deficient hematopoietic stem cells. Based on the close association of PNH with aplastic anemia, it has been suggested that the selection pressure is immune mediated. However, in spite that over 60% of patients with aplastic anemia have subclinical population of GPI-deficient hematopoietic cells at diagnosis, only 10% develop clinical PNH, suggesting that steps-1 and 2 are insufficient to cause PNH. Under immune mediated selection pressure, GPI-deficient cells not only survive, but also must proliferate much more frequently than usual to compensate for anemia. This elevated proliferation rate may increase a chance that additional mutations are acquired, in turn leads to step 3. Step 3 involves a second somatic mutation that bestows on PIG-A mutant stem cell a proliferative phenotype. According to this hypothesis, we searched for the candidate gene for step 3. We reported 2 patients with PNH whose PIG-A mutant cells had an acquired rearrangement of chromosome12, generating the break within the 3′ untranslated region in HMGA2. This gene encodes an architectural transcription factor which is deregulated in many benign mesenchymal tumors (Blood. 2006 vol.108 no.13, p4232). Based on these, we consider HMGA2 as a candidate gene, ectopic expression of which causes proliferation of PIG-A mutant cells. We reported that the expression of HMGA2 in peripheral blood from PNH patients was significantly higher than that from normal volunteers (relative mRNA expression, 4.8±2.4 vs 1.3±0.3, p<0.05) but this was not the case in the bone marrow. We investigated whether over expression of HMGA2 really causes the clonal expansion using the mouse model. We transduced the mouse bone marrow cells with retrovirus vectors, pMYs-HMGA2-IRES-EGFP or pMY-IRES-EGFP as a control, and transplanted them into lethally irradiated mice. The percentage of HMGA2 expressing cells in peripheral blood cells of each lineage from transplanted mice gradually increased during 4-months' observation, suggesting that over expression of HMGA2 caused clonal expansion of multipotent hematopoietic cells. This result is consistent with a recent report on the gene therapy of beta-thalathemia that clonal expansion of rescued hematopoietic cells occurred due to lentivaral insertion into and ectopic expression of HMGA2 (Science. 2009, 326, p1468). Investigation of the somatic mutation which causes upregulation of HMGA2 is being conducted. The dysregulation of Wnt pathway is one of the candidate mechanisms (Blood. 2009, vol.114, no.22, p786). These results are consistent with our 3-step model of PNH pathogenesis, that is, clonal expansion is caused not only by survival advantage from immunological attack but also by benign-tumor-like proliferation. Disclosures: No relevant conflicts of interest to declare.


1995 ◽  
Vol 104 (6) ◽  
pp. 928-932 ◽  
Author(s):  
Yoshio Urano ◽  
Takashi Asano ◽  
Katsuhiko Yoshimoto ◽  
Hiroyuki Iwahana ◽  
Yoshiaki Kubo ◽  
...  

2017 ◽  
Vol 58 (8) ◽  
pp. 592-606 ◽  
Author(s):  
Takafumi Nakayama ◽  
Tomoko Sawai ◽  
Ikuko Masuda ◽  
Shinya Kaneko ◽  
Kazumi Yamauchi ◽  
...  

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