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. 2025 Apr 7;222(4):e20231349.
doi: 10.1084/jem.20231349. Epub 2025 Feb 19.

Native stem cell transcriptional circuits define cardinal features of high-risk leukemia

Qing Wang #  1 , Francesco Boccalatte #  2   3 , Jason Xu #  4 , Giovanni Gambi  2 , Bettina Nadorp  2   5 , Fatema Akter  1 , Carea Mullin  1 , Ashley F Melnick  6 , Elizabeth Choe  7 , Anna C McCarter  8 , Nicole A Jerome  9 , Siyi Chen  1 , Karena Lin  6 , Sarah Khan  1 , Rohan Kodgule  10 , Jonathan H Sussman  4 , Petri Pölönen  11 , Javier Rodriguez-Hernaez  2   5 , Sonali Narang  2 , Kleopatra Avrampou  2 , Bryan King  2 , Aristotelis Tsirigos  2   5 , Russell J H Ryan  10 , Charles G Mullighan  11 , David T Teachey  12 , Kai Tan  12 , Iannis Aifantis  2   13 , Mark Y Chiang  1
Affiliations

Native stem cell transcriptional circuits define cardinal features of high-risk leukemia

Qing Wang et al. J Exp Med. .

Abstract

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.

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Conflict of interest statement

Disclosures: C.G. Mullighan reported personal fees from Illumina during the conduct of the study; personal fees from Amgen, grants from Pfizer, and grants from Abbvie outside the submitted work. D.T. Teachey reported grants from BEAM Therapeutics, non-financial support from Sobi, non-financial support from J&J, non-financial support from Servier, non-financial support from Jazz, non-financial support from Amgen, grants from Neoimmune Tech, and non-financial support from Novartis outside the submitted work. No other disclosures were reported.

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