Three novel fusion transcripts of the paired box 5 gene in B-cell precursor acute lymphoblastic leukemia.
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ABSTRACT:
SUBMITTER: Fazio G
PROVIDER: S-EPMC4281328 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
Publications
Three novel fusion transcripts of the paired box 5 gene in B-cell precursor acute lymphoblastic leukemia.
Fazio Grazia G Daniele Giulia G Cazzaniga Valeria V Impera Luciana L Severgnini Marco M Iacobucci Ilaria I Galbiati Marta M Leszl Anna A Cifola Ingrid I De Bellis Gianluca G Bresciani Paola P Martinelli Giovanni G Basso Giuseppe G Biondi Andrea A Storlazzi Clelia Tiziana CT Cazzaniga Giovanni G
Haematologica 20141010 1
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Project description:The cellular context that integrates gene expression, signaling, and metabolism dictates the oncogenic behavior and shapes the treatment responses in distinct cancer types. Although chimeric fusion proteins involving transcription factors (TF) are hallmarks of many types of acute lymphoblastic leukemia (ALL), therapeutically targeting the fusion proteins is a challenge. In this work, we characterize the core regulatory circuitry (CRC; interconnected autoregulatory loops of TFs) of B-ALL involving MEF2D-fusions and identify MEF2D-fusion and SREBF1 TFs as crucial CRC components. By gene silencing and pharmacologic perturbation, we reveal that the CRC integrates the pre-B-cell receptor (BCR) and lipid metabolism to maintain itself and govern malignant phenotypes. Small-molecule inhibitors of pre-BCR signaling and lipid biosynthesis disrupt the CRC and silence the MEF2D fusion in cell culture and show therapeutic efficacy in xenografted mice. Therefore, pharmacologic disruption of CRC presents a potential therapeutic strategy to target fusion protein-driven leukemia.SignificanceCancer type-specific gene expression is governed by transcription factors involved in a highly interconnected autoregulatory loop called CRC. Here, we characterized fusion protein-driven CRC and identified its pharmacologic vulnerabilities, opening therapeutic avenues to indirectly target fusion-driven leukemia by disrupting its CRC.See related commentary by Sadras and Müschen, p. 18. This article is highlighted in the In This Issue feature, p. 5.
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