@misc{10481/81598,
year = {2023},
month = {3},
url = {https://hdl.handle.net/10481/81598},
abstract = {Background Recent massive sequencing studies have revealed that SWI/SNF complexes are among the most fre‑
quently altered functional entities in solid tumors. However, the role of SWI/SNF in acute myeloid leukemia is poorly
understood. To date, SWI/SNF complexes are thought to be oncogenic in AML or, at least, necessary to support leuke‑
mogenesis. However, mutation patterns in SWI/SNF genes in AML are consistent with a tumor suppressor role. Here,
we study the SWI/SNF subunit BCL7A, which has been found to be recurrently mutated in lymphomas, but whose
role in acute myeloid malignancies is currently unknown.
Methods Data mining and bioinformatic approaches were used to study the mutational status of BCL7A and the
correlation between BCL7A expression and promoter hypermethylation. Methylation‑specific PCR, bisulfite sequenc‑
ing, and 5‑aza‑2’‑deoxycytidine treatment assays were used to determine if BCL7A expression was silenced due to
promoter hypermethylation. Cell competition assays after BCL7A expression restoration were used to assess the role
of BCL7A in AML cell line models. Differential expression analysis was performed to determine pathways and genes
altered after BCL7A expression restoration. To establish the role of BCL7A in tumor development in vivo, tumor growth
was compared between BCL7A‑expressing and non‑expressing mouse xenografts using in vivo fluorescence imaging.
Results BCL7A expression was inversely correlated with promoter methylation in three external cohorts: TCGA‑LAML
(N = 160), TARGET‑AML (N = 188), and Glass et al. (2017) (N = 111). The AML‑derived cell line NB4 silenced the BCL7A
expression via promoter hypermethylation. Ectopic BCL7A expression in AML cells decreased their competitive ability
compared to control cells. Additionally, restoration of BCL7A expression reduced tumor growth in an NB4 mouse
xenograft model. Also, differential expression analysis found that BCL7A restoration altered cell cycle pathways and
modified significantly the expression of genes like HMGCS1, H1-0, and IRF7 which can help to explain its tumor sup‑
pressor role in AML.
Conclusions BCL7A expression is silenced in AML by promoter methylation. In addition, restoration of BCL7A expres‑
sion exerts tumor suppressor activity in AML cell lines and xenograft models.},
organization = {Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía and FEDER (P20‑00688)},
organization = {Ministry of Science and Innovation of Spain (grant PID2021‑126111OB‑I00)},
organization = {Junta de Andalucía (grants PIGE‑0440–2019, PI‑0135–2020)},
organization = {University of Granada (B‑CTS‑126‑UGR18, B‑CTS‑480‑UGR20, E‑CTS‑304‑UGR20)},
organization = {Spanish Association for Cancer Research (LABORATORY‑AECC‑2018)},
organization = {Spanish Ministry of Science, Innovation and Universities FPU18/03709, FPU17/00067, FPU19/00576},
publisher = {Springer Nature},
keywords = {SWI/SNF complex},
keywords = {AML},
keywords = {Tumor suppresso},
keywords = {DNA hypermethylation},
title = {BCL7A is silenced by hypermethylation to promote acute myeloid leukemia},
doi = {10.1186/s40364-023-00472-x},
author = {Patiño Mercau, Juan Rodrigo and Andrades, Alvaro and Maria S., Benitez‑Cantos and Rodríguez Lara, María Isabel and Álvarez Pérez, Juan Carlos and Cuadros Celorrio, Marta Eugenia and Medina Vico, Pedro Pablo},
}