The Journal of experimental medicine · 2025
Native stem cell transcriptional circuits define cardinal features of high-risk leukemia.
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Wang Qing, Boccalatte Francesco, Xu Jason, Gambi Giovanni, Nadorp Bettina, Akter Fatema, Mullin Carea, Melnick Ashley F, Choe Elizabeth, McCarter Anna C, Jerome Nicole A, Chen Siyi, Lin Karena, Khan Sarah, Kodgule Rohan, Sussman Jonathan H, Pölönen Petri, Rodriguez-Hernaez Javier, Narang Sonali, Avrampou Kleopatra, King Bryan, Tsirigos Aristotelis, Ryan Russell J H, Mullighan Charles G, Teachey David T, Tan Kai, Aifantis Iannis, Chiang Mark Y
Аннотация
While the mutational landscape across early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) and ETP-like leukemia is known, establishing a unified framework that activates stem cell genes characteristic of these tumors remains elusive. Using complementary mouse and human models, chromatin mapping, and enhancer profiling, we show that the coactivator ZMIZ1 promotes normal and malignant ETP population growth by inducing the transcription factor MYB in feedforward circuits to convergently activate oncogenes (MEF2C, MYCN, and BCL2) through essential enhancers. A key superenhancer, the N-Myc regulating enhancer (NMRE), drives malignant ETP population growth but is dispensable for normal lymphopoiesis. This network of stem cell superenhancers identifies treatment-resistant tumors and poor survival outcomes; unifies diverse ETP-ALLs; and contributes to cardinal features of the recently genomically identified high-risk bone marrow progenitor-like (BMP-like) ETP-ALL tumor-stem cell/myeloid gene expression, inhibited NOTCH1-induced T-cell development, aggressive clinical behavior, and venetoclax sensitivity. Since ZMIZ1 is dispensable for essential homeostasis, it might be possible to safely target this network to treat high-risk diseases.