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