Abstract

Chronic myeloid leukemia (CML) is a blood cancer characterized by dysregulated production of maturing myeloid cells driven by the product of the Philadelphia chromosome, the BCR-ABL1 tyrosine kinase. Tyrosine kinase inhibitors (TKI) have proved effective in treating CML but there is still a cohort of patients who do not respond to TKI therapy even in the absence of mutations in the BCR-ABL1 kinase domain that mediate drug resistance. To discover novel strategies to improve TKI therapy in CML, we developed a nonlinear mathematical model of CML hematopoiesis that incorporates feedback control and lineage branching. Cell-cell interactions were constrained using an automated model selection method together with previous observations and new in vivo data from a chimeric BCR-ABL1 transgenic mouse model of CML. The resulting quantitative model captures the dynamics of normal and CML cells at various stages of the disease and exhibits variable responses to TKI treatment, consistent with those of CML patients. The model predicts that an increase in the proportion of CML stem cells in the bone marrow would decrease the tendency of the disease to respond to TKI therapy, in concordance with clinical data and confirmed experimentally in mice. The model further suggests that, under our assumed similarities between normal and leukemic cells, a key predictor of refractory response to TKI treatment is an increased maximum probability of self-renewal of normal hematopoietic stem cells. We use these insights to develop a clinical prognostic criterion to predict the efficacy of TKI treatment and to design strategies to improve treatment response. The model predicts that stimulating the differentiation of leukemic stem cells while applying TKI therapy can significantly improve treatment outcomes.

Data availability

Modelling code and parameter set data are available in a Github repository. Patient data is unavailable publicly as it could be used to potentially identify the patients. Deidentified raw patient transcript data will be made available to qualified researchers (academic or industry) upon request to Dr. Van Etten at vanetten@hs.uci.edu.

The following data sets were generated

Article and author information

Author details

  1. Jonathan Rodriguez

    Graduate Program in Mathematical, Computational and Systems Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6414-0526
  2. Abdon Iniguez

    Graduate Program in Mathematical, Computational and Systems Biology, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Nilamani Jena

    Department of Medicine, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Prasanthi Tata

    Department of Medicine, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Joan Liu

    Department of Medicine, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Arthur D Lander

    Center for Complex Biological Systems, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4380-5525
  7. John S Lowengrub

    Department of Mathematics, University of California, Irvine, Irvine, United States
    For correspondence
    lowengrb@math.uci.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1759-0900
  8. Richard A Van Etten

    Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, United States
    For correspondence
    vanetten@hs.uci.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (1U54CA217378-01A1)

  • Arthur D Lander
  • John S Lowengrub
  • Richard A Van Etten

National Institutes of Health (P30CA062203)

  • Arthur D Lander
  • John S Lowengrub
  • Richard A Van Etten

National Institutes of Health (R01 CA090576)

  • Richard A Van Etten

National Science Foundation (DMS-1763272)

  • Arthur D Lander
  • John S Lowengrub

National Science Foundation (DMS-1936833)

  • John S Lowengrub

National Science Foundation (DMS-1953410)

  • John S Lowengrub

National Science Foundation (GRFP 16-588)

  • Abdon Iniguez

Simons Foundation (594598QN)

  • Arthur D Lander
  • John S Lowengrub

National Institute of General Medical Sciences (GM136624)

  • Jonathan Rodriguez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (AUP-19-159) of the University of California, Irvine.

Copyright

© 2023, Rodriguez et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 582
    views
  • 130
    downloads
  • 4
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Jonathan Rodriguez
  2. Abdon Iniguez
  3. Nilamani Jena
  4. Prasanthi Tata
  5. Joan Liu
  6. Arthur D Lander
  7. John S Lowengrub
  8. Richard A Van Etten
(2023)
Predictive nonlinear modeling of malignant myelopoiesis and tyrosine kinase inhibitor therapy
eLife 12:e84149.
https://doi.org/10.7554/eLife.84149

Share this article

https://doi.org/10.7554/eLife.84149

Further reading

    1. Cancer Biology
    Qianqian Ju, Wenjing Sheng ... Cheng Sun
    Research Article

    TAK1 is a serine/threonine protein kinase that is a key regulator in a wide variety of cellular processes. However, the functions and mechanisms involved in cancer metastasis are still not well understood. Here, we found that TAK1 knockdown promoted esophageal squamous cancer carcinoma (ESCC) migration and invasion, whereas TAK1 overexpression resulted in the opposite outcome. These in vitro findings were recapitulated in vivo in a xenograft metastatic mouse model. Mechanistically, co-immunoprecipitation and mass spectrometry demonstrated that TAK1 interacted with phospholipase C epsilon 1 (PLCE1) and phosphorylated PLCE1 at serine 1060 (S1060). Functional studies revealed that phosphorylation at S1060 in PLCE1 resulted in decreased enzyme activity, leading to the repression of phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. As a result, the degradation products of PIP2 including diacylglycerol (DAG) and inositol IP3 were reduced, which thereby suppressed signal transduction in the axis of PKC/GSK-3β/β-Catenin. Consequently, expression of cancer metastasis-related genes was impeded by TAK1. Overall, our data indicate that TAK1 plays a negative role in ESCC metastasis, which depends on the TAK1-induced phosphorylation of PLCE1 at S1060.

    1. Cancer Biology
    2. Cell Biology
    Rui Hua, Jean X Jiang
    Insight

    Cell crowding causes high-grade breast cancer cells to become more invasive by activating a molecular switch that causes the cells to shrink and spread.