Stanford
Center for Cancer Systems Biology

Tipping Points in Cancer: Collective, non-mutational transitions in CML initiation

John Lowengrub, PhD - University of California, Irvine

Event Details:

Friday, October 17, 2025
11:00am - 12:00pm PDT

Location

Clark Center, Room S360, 3rd floor
Stanford, CA 94305
United States

Presentation Recording

Abstract

Although the initiation of cancer typically depends on the accumulation of somatic mutations, evidence increasingly suggests that non-genetic mechanisms, such as epigenetic alterations and cell interactions, also contribute to malignant transformation. Here, we describe a model of chronic myeloid leukemia (CML) that activates expression of the BCR::ABL1 fusion oncogene in subsets of hematopoietic stem cells in otherwise wildtype mice, facilitating investigation of early events in CML pathogenesis. We observe a latent period in leukemogenesis consistent with stochastic initiation, the duration of which depends on the fraction of leukemic hematopoietic stem cells (HSCL) in the bone marrow. Remarkably, below a threshold level (~4% HSCL), leukemia does not occur despite persistence of the mutated clones. When leukemias do arise, they are clonally diverse and not associated with the appearance of new, potentially causal mutations. Adapting a mathematical model of CML myelopoiesis previously developed to study responses to tyrosine kinase inhibitor (TKI) therapy, we show that a combination of negative feedback (at least partially mediated by p19Arf-dependent replicative stress) and intercellular positive feedback are sufficient to explain both the dynamics and threshold behavior of leukemogenesis in these mice. To our knowledge this is the first documented example of a collective cell behavior explaining a non-genetic transition in cancer initiation, a result that has significant implications for understanding CML development and improving therapy. 

Bio

Dr. Lowengrub is a systems biologist and mathematician whose research efforts focus on developing mathematically rigorous and biologically-justified models of tumor growth. Dr. Lowengrub’s research aims to use data-driven mathematical modeling, high-performance computation, and statistical inference methodologies to understand how feedback signaling, metabolic reprogramming, mechanical forces and interactions between tumor cells, and immune and stromal cells in its microenvironment can drive tumor progression and the development of new treatment strategies. Dr. Lowengrub co-authored the monograph Multiscale Modeling of Cancer: An Integrated Experimental and Mathematical Modeling Approach. Dr. Lowengrub has mentored more than 100 trainees, including high school, undergraduate, graduate and postdoctoral researchers. Dr. Lowengrub is the founding Director of the interdisciplinary MS/PhD program in Mathematical, Computational and Systems Biology and is an Associate Director of the NSF-Simons Foundation Center for Multiscale Cell Fate Research where he oversees outreach and education activities. Dr. Lowengrub served as the co-Director of the NCI-CSBC UC Irvine Center for Cancer Systems Biology and he currently serves as the contact MPI for a NCI-P01 program project focused on tipping points in cancer. Dr. Lowengrub also serves as Program Co-Leader of the Systems, Pathways and Targets (SPT) Program at the Chao Family Comprehensive Cancer Center at UC Irvine where brings together systems and cancer biologists to integrate systems biology approaches in cancer.

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