Mutations at BCL11B Exon 4 Associated with T Cell Acute Lymphoblastic Leukemia Are Facilitated by AID and Formation of Non-B DNA Conformations

Roy, U and Sharma, A and Sharma, S and Dahal, S and Kumari, N and Desai, SS and Kumari, S and Dixit, J and Sharma, AM and Nujoom, N and Choudhary, B and Raghavan, SC (2024) Mutations at BCL11B Exon 4 Associated with T Cell Acute Lymphoblastic Leukemia Are Facilitated by AID and Formation of Non-B DNA Conformations. In: Molecular and Cellular Biology, 44 (12). pp. 590-606.

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Abstract

One of the primary reasons behind the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL) is the deregulation of the transcription factor BCL11B. The exon 4 of BCL11B harbors several driver mutations, which abolishes its DNA-binding ability. The high frequency of C > T or G > A conversion in close vicinity of AID (Activation-induced cytidine deaminase)-hotspot motifs in the deregulated gene prompted us to investigate the role of AID in BCL11B mutagenesis. Our results reveal that AID is expressed in T-ALL patient-derived cells, binds to BCL11B fragile region (FR) in exon 4 of T cells in vivo, and generates a signature mutation pattern in this region. The mutation frequency in BCL11B FR could be modulated upon overexpression of the AID gene in the knockout background, further suggesting the involvement of AID in BCL11B mutagenesis. Importantly, various lines of experimentation reveal that BCL11B FR could fold into parallel G-quadruplex, triplex, and hairpin structures, which could act as a replication/transcription block, causing mutagenesis. Thus, our results suggest that AID binds to BCL11B exon 4 due to non-B DNA formation, causing U:G mismatches or replication blocks, which, when repaired erroneously, generates deleterious mutations, resulting in loss of functionality of BCL11B, and thus becomes the cause of T-ALL. © 2024 Taylor & Francis Group, LLC.

Item Type:	Journal Article
Publication:	Molecular and Cellular Biology
Publisher:	Taylor and Francis Ltd.
Additional Information:	The copyright for this article belongs to Molecular and Cellular Biology
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	17 Dec 2024 04:08
Last Modified:	17 Dec 2024 04:08
URI:	http://eprints.iisc.ac.in/id/eprint/87056

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