Studying the age of onset and detection of Chronic Myeloid Leukemia using a three-stage stochastic model

TL;DR

This paper introduces a three-stage stochastic model for CML progression, aligning predictions with US age incidence data and providing a framework to estimate the malignancy onset time from detection.

Contribution

It develops a novel three-mutation stochastic model for CML that captures disease progression and enables retrospective estimation of cancer onset.

Findings

Model predictions match US age incidence data.

Framework for estimating malignancy onset from detection.

Highlights the role of additional mutations beyond BCR-ABL.

Abstract

Chronic Myeloid Leukemia (CML) is a biphasic malignant clonal disorder that progresses, first with a chronic phase, where the cells have enhanced proliferation only, and then to a blast phase, where the cells have the ability of self-renewal. It is well-recognized that the Philadelphia chromosome (which contains the BCR-ABL fusion gene) is the "hallmark of CML". However, empirical studies have shown that the mere presence of BCR-ABL may not be a sufficient condition for the development of CML, and further modifications related to tumor suppressors may be necessary. Accordingly, we develop a three-mutation stochastic model of CML progression, with the three stages corresponding to the non-malignant cells with BCR-ABL presence, the malignant cells in the chronic phase and the malignant cells in the blast phase. We demonstrate that the model predictions agree with age incidence data from the United States. Finally, we develop a framework for the retrospective estimation of the time of onset of malignancy, from the time of detection of the cancer.