Tumor suppressor-like mutations mark a dosage-constrained dependency in leukemia

Abstract

Cancer genes are classically categorized as oncogenes or tumor suppressors based on whether gain or loss of function promotes malignancy. Here we show that oncogene-imposed dosage constraints can produce mutations that mimic tumor suppressor loss yet mark essential genes. In acute promyelocytic leukemia (APL), the transcription factor EBF3 gene harbors recurrent heterozygous loss-of-function mutations, a tumor suppressor signature, and is essential for APL survival. We resolve this paradox by showing that while PML::RARA, the fusion oncoprotein defining APL, drives EBF3 expression, excess EBF3 suppresses proliferation. Patient mutations reduce EBF3 activity through heterozygous inactivation, optimizing its expression within a corridor bounded by fitness constraints at both extremes. PML::RARA activates EBF3 via a p300-dependent intronic enhancer, and p300 inhibition exploits this constraint by suppressing EBF3 below the viability threshold. Our findings reveal that oncogenes can impose dosage constraints that drive adaptive mutations conventionally misclassified as tumor suppressor loss, with implications for interpreting cancer genomes.

Ascorbate is a physiological tumor suppressor metabolite in leukemia
T. Wijshake, J. Rose, J. H. Jun +10
bioRxiv20 Oct 2026PreprintCC BY-NC-NDFull textOncologybioRxivPMC
SMARCA4 MUTATIONS PROMOTE CHEMOTHERAPY RESISTANCE IN T-ACUTE LYMPHOBLASTIC LEUKEMIA THROUGH ALTERED CHROMATIN REMODELING AT AP1-ASSOCIATED REGULATORY REGIONS
V. Garcia-Hernandez, M. Maqueda, G. Faccincani +10
bioRxiv1 Nov 2026PreprintAll rights reservedFull textOncologybioRxiv
ATM Gene Mutations in Iraqi Patients with Chronic Lymphocytic Leukemia Patients in Kurdistan Region -Iraq
Chra Fadhil Kudhur, Kazhal Muhammad Sulaiman
Tikrit Journal of Pure Science25 Oct 2026Peer-reviewedCC BYFull textHuman geneticsDOAJ
Acute monocytic leukemia with t(8;22)(p11;q11)/BCR::FGFR1, trisomy 8, and concurrent RUNX1/STAG2 mutations: A rare case report and literature review.
Surya Prakash Rao Kunda, Sambasivarao Patibandla, Rajesh Mallik Gottipati +4
Leukemia research reports10 Oct 2026Peer-reviewedCC BY-NC-NDFull textGeneral medicineEurope PMC
FOXM1 as a candidate dosage rheostat and state selector in breast cancer: linking multilevel regulation to adaptive plasticity and therapy resistance
Ghaleb Oriquat, Hani Moslem Ahmed, Jasur Rizaev +4
Frontiers in oncology16 Oct 2026Peer-reviewedCC BYFull textOncologyEurope PMC

Cite

BibTeX RIS

BibTeX

@misc{lee2026tumor,
  title = {{Tumor suppressor-like mutations mark a dosage-constrained dependency in leukemia}},
  author = {J. D. Lee and M. M. Uyemura and F. Lamini and R. R. Posey and E. H. Shin and A. C. Harris and T. Ottone and G. Cheloni and D. B. Chou and B. Q. Trinh and J. A. Paulo and D. G. Tenen and J. G. Clohessy and M. T. Voso and T. A. Graubert and F. J. Slack},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.29.755484},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.29.755484v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Tumor suppressor-like mutations mark a dosage-constrained dependency in leukemia
AU  - J. D. Lee
AU  - M. M. Uyemura
AU  - F. Lamini
AU  - R. R. Posey
AU  - E. H. Shin
AU  - A. C. Harris
AU  - T. Ottone
AU  - G. Cheloni
AU  - D. B. Chou
AU  - B. Q. Trinh
AU  - J. A. Paulo
AU  - D. G. Tenen
AU  - J. G. Clohessy
AU  - M. T. Voso
AU  - T. A. Graubert
AU  - F. J. Slack
PY  - 2026
DA  - 2026/09/29
PB  - bioRxiv
DO  - 10.64898/2026.09.29.755484
UR  - https://www.biorxiv.org/content/10.64898/2026.09.29.755484v1
AB  - Cancer genes are classically categorized as oncogenes or tumor suppressors based on whether gain or loss of function promotes malignancy. Here we show that oncogene-imposed dosage constraints can produce mutations that mimic tumor suppressor loss yet mark essential genes. In acute promyelocytic leukemia (APL), the transcription factor EBF3 gene harbors recurrent heterozygous loss-of-function mutations, a tumor suppressor signature, and is essential for APL survival. We resolve this paradox by showing that while PML::RARA, the fusion oncoprotein defining APL, drives EBF3 expression, excess EBF3 suppresses proliferation. Patient mutations reduce EBF3 activity through heterozygous inactivation, optimizing its expression within a corridor bounded by fitness constraints at both extremes. PML::RARA activates EBF3 via a p300-dependent intronic enhancer, and p300 inhibition exploits this constraint by suppressing EBF3 below the viability threshold. Our findings reveal that oncogenes can impose dosage constraints that drive adaptive mutations conventionally misclassified as tumor suppressor loss, with implications for interpreting cancer genomes.
ER  -

Abstract

Related

Cite