RT Journal Article SR Electronic T1 Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia JF Blood Cancer Discovery JO Blood Cancer Discov FD American Association for Cancer Research SP 82 OP 95 DO 10.1158/2643-3230.BCD-19-0080 VO 1 IS 1 A1 Tsuzuki, Shinobu A1 Yasuda, Takahiko A1 Kojima, Shinya A1 Kawazu, Masahito A1 Akahane, Koshi A1 Inukai, Takeshi A1 Imaizumi, Masue A1 Morishita, Takanobu A1 Miyamura, Koichi A1 Ueno, Toshihide A1 Karnan, Sivasundaram A1 Ota, Akinobu A1 Hyodo, Toshinori A1 Konishi, Hiroyuki A1 Sanada, Masashi A1 Nagai, Hirokazu A1 Horibe, Keizo A1 Tomita, Akihiro A1 Suzuki, Kyogo A1 Muramatsu, Hideki A1 Takahashi, Yoshiyuki A1 Miyazaki, Yasushi A1 Matsumura, Itaru A1 Kiyoi, Hitoshi A1 Hosokawa, Yoshitaka A1 Mano, Hiroyuki A1 Hayakawa, Fumihiko YR 2020 UL http://bloodcancerdiscov.aacrjournals.org/content/1/1/82.abstract AB 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.Significance: Cancer 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