Targeting MEF2D-fusion Oncogenic Transcriptional Circuitries in B-cell Precursor Acute Lymphoblastic Leukemia.

Abstract

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.

• Authors: Shinobu Tsuzuki, Takahiko Yasuda, Shinya Kojima, Masahito Kawazu, Koshi Akahane, Takeshi Inukai, Masue Imaizumi, Takanobu Morishita, Koichi Miyamura, Toshihide Ueno, Sivasundaram Karnan, Akinobu Ota, Toshinori Hyodo, Hiroyuki Konishi, Masashi Sanada, Hirokazu Nagai, Keizo Horibe, Akihiro Tomita, Kyogo Suzuki, Hideki Muramatsu, Yoshiyuki Takahashi, Yasushi Miyazaki, Itaru Matsumura, Hitoshi Kiyoi, Yoshitaka Hosokawa, Hiroyuki Mano, Fumihiko Hayakawa
• Journal: Blood cancer discovery (Blood Cancer Discov) Vol. 1 Issue 1 Pg. 82-95 (Jul 2020) ISSN: 2643-3249 [Electronic] United States
• PMID: 34661142 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• MEF2 Transcription Factors
• Mef2d protein, mouse
• Oncogene Proteins, Fusion

Topics

• Animals
• Gene Fusion
• MEF2 Transcription Factors (genetics)
• Mice
• Oncogene Proteins, Fusion (genetics)
• Oncogenes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (genetics)