Somatic human ZBTB7A zinc finger mutations promote cancer progression

Liu, XS; Z, Liu; Gerarduzzi, Casimiro; Choi, Dae Eun; Ganapathy, Suthakar; Pandolfi, Pier Paolo; Zhang, Yuan

doi:10.1038/onc.2015.371

Cited by 31 publications

(35 citation statements)

References 25 publications

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“…1a), as already described in other readouts [1]. Despite a previous report in the context of colon cancer suggesting that ZBTB7A zinc finger mutations act in a dominant negative manner [22], we could not find any evidence for this effect in our models, even when the expression of the R402C mutant was slightly higher than the control (Fig. 1e).…”

Section: Zbtb7a Causes Cell Cycle Arrestsupporting

confidence: 59%

ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells

et al. 2020

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ZBTB7A is frequently mutated in acute myeloid leukemia (AML) with t(8;21) translocation. However, the oncogenic collaboration between mutated ZBTB7A and the RUNX1-RUNX1T1 fusion gene in AML t(8;21) remains unclear. Here, we investigate the role of ZBTB7A and its mutations in the context of normal and malignant hematopoiesis. We demonstrate that clinically relevant ZBTB7A mutations in AML t(8;21) lead to loss of function and result in perturbed myeloid differentiation with block of the granulocytic lineage in favor of monocytic commitment. In addition, loss of ZBTB7A increases glycolysis and hence sensitizes leukemic blasts to metabolic inhibition with 2-deoxy-D-glucose. We observed that ectopic expression of wild-type ZBTB7A prevents RUNX1-RUNX1T1-mediated clonal expansion of human CD34+ cells, whereas the outgrowth of progenitors is enabled by ZBTB7A mutation. Finally, ZBTB7A expression in t(8;21) cells lead to a cell cycle arrest that could be mimicked by inhibition of glycolysis. Our findings suggest that loss of ZBTB7A may facilitate the onset of AML t(8;21), and that RUNX1-RUNX1T1-rearranged leukemia might be treated with glycolytic inhibitors.

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Section: Zbtb7a Causes Cell Cycle Arrestsupporting

confidence: 59%

ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells

et al. 2020

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“…Overexpression of Zbtb 7a in murine prostate epithelium did not result in neoplastic transformation; unexpectedly, Zbtb7a inactivation lead to the acceleration of Pten-driven prostate tumorigenesis 20 . Recently, somatic zinc-finger mutations of ZBTB7A were found at low frequencies (<5%) in a variety of solid cancers suggesting a common mechanism across tumour entities 21 . In fact, the de-repression of glycolytic genes upon deletion or mutation of ZBTB7A 10 21 might underlie the loss of anti-proliferative properties that we observed for ZBTB7A mutants A175fs and R402C in the present study.…”

Section: Discussionmentioning

confidence: 99%

ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation

et al. 2016

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The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion.

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“…These values are significantly higher compared to that of RACER network with 12 and 9 degrees. Previous studies [50,51] have shown that ZBTB7A functions as a transcriptional suppressor. ZBTB7A was also proven to play a critical role in AML as a transcription factor in [52].…”

Section: Results For Dream4mentioning

confidence: 95%

An Order Independent Algorithm for Inferring Gene Regulatory Network Using Quantile Value for Conditional Independent Tests

Mahmoodi

Aghdam

Eslahchi

2020

Preprint

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Background: In recent years, due to the difficulty and inefficiency of experimental methods, numerous computational methods have been introduced for inferring structure of Gene Regulatory Networks (GRNs). Bayesian network is one of the popular methods in this field, however, still has many drawbacks and there is still a great space to be improved. For example, the Path Consistency (PC)-based algorithms as Bayesian network methods are still sensitive to the ordering of nodes i.e. different node orders results in different network structures. The second is that the networks inferred by these methods are highly dependent on the threshold used for independence testing. Also, it is still a challenge to select the set of conditional genes in an optimal way, which affects the performance and computation complexity of the PC-based algorithm. Results: We introduce a novel algorithm, namely Order Independent PC-based algorithm using Quantile value (OIPCQ), which improves the accuracy of the learning process of GRNs and solves the order dependency issue. The quantile-based thresholds are considered for different order of CMI test. For conditional gene selection, we consider the paths between genes with length equal or greater than 2 while others well-known PC-based methods only considers the paths of length 2. We applied OIPCQ on the various networks of the DREAM3 and DREAM4 in silico challenges. As a real-world case study, we used OIPCQ to reconstruct SOS DNA network obtained from Escherichia coli and GRN for acute myeloid leukemia based on the RNA sequencing data from The Cancer Genome Atlas. The results show that OIPCQ produces the same network structure for all the permutations of the genes and improves the resulted GRN through accurately quantifying the causal regulation strength in comparison with others well-known PC-based methods. Conclusions: According to the GRN constructed by OIPCQ, for acute myeloid leukemia, two regulators BCLAF1 and NRSF reported by Zhang et al are significantly important. However, the highest degree nodes in this GRN are ZBTB7A and PU1 which play a significant role in cancer, and especially in leukemia. OIPCQ is freely accessible at https://github.com/haammim/OIPCQ-and-OIPCQ2.

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Somatic human ZBTB7A zinc finger mutations promote cancer progression

Cited by 31 publications

References 25 publications

ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells

ZBTB7A prevents RUNX1-RUNX1T1-dependent clonal expansion of human hematopoietic stem and progenitor cells

ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation

An Order Independent Algorithm for Inferring Gene Regulatory Network Using Quantile Value for Conditional Independent Tests

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