Determining the role of inflammation in the selection of JAK2 mutant cells in myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2V617F). This mutation endows upon myeloid progenitors cytokine independent growth and consequently leads to excessive production of myeloid lineage cells. It has been previously suggested that inflammation may play a role in the clonal evolution of JAK2V617F mutants. In particular, it is possible that one or more cellular kinetic parameters of hematopoietic stem cells (HSCs) are affected by inflammation, such as division or death rates of cells, and the probability of HSC differentiation. This suggests a mechanism that can steer the outcome of the cellular competition in favor of the mutants, initiating the disease. In this paper we create a number of mathematical evolutionary models, from very abstract to more concrete, that describe cellular competition in the context of inflammation. It is possible to build a model axiomatically, where only very general assumptions are imposed on the modeling components and no arbitrary (and generally unknown) functional forms are used, and still generate a set of testable predictions. In particular, we show that, if HSC death is negligible, the evolutionary advantage of mutant cells can only be conferred by an increase in differentiation probability of HSCs in the presence of inflammation, and if death plays a significant role in the dynamics, an additional mechanism may be an increase of HSC’s division-to-death ratio in the presence of inflammation. Further, we show that in the presence of inflammation, the wild type cell population is predicted to shrink under inflammation (even in the absence of mutants). Finally, it turns out that if only the differentiation probability is affected by the inflammation, then the resulting steady state population of wild type cells will contain a relatively smaller percentage of HSCs under inflammation. If the division-to-death rate is also affected, then the percentage of HSCs under inflammation can either decrease or increase, depending on other parameters.

Mathematical Modeling of MPNs Offers Understanding and Decision Support for Personalized Treatment

“…Our results are more comprehensive than the previously presented results in [17,18], mainly due to the high-quality data over five years, which allow for more and better analyses. Thus, the complex relation between data and mathematical modeling calls for a close collaboration between clinicians and mathematicians in order to increase the scientific insights into the JAK2V617F kinetics and response to treatment.…”

“…Mathematical modelling plays an important role in the study of cancer [13][14][15][16], but only a few studies have addressed MPNs [17,18]. In the present paper, we apply a patient-specific mechanism-based mathematical model, the Cancitis model [19][20][21], to study the dynamics of Philadelphia chromosome-negative, JAK2V617F-positive MPN patients from the DALIAH trial.…”

The Critical Role of Inflammation in the Pathogenesis and Progression of Myeloid Malignancies

“…Mathematical modeling can be used as an approach to help define how specific pressures lead to the selective outgrowth of neoplastic HSC clones. Multiple investigators have modeled the effects of inflammation on MPN mutant versus wild-type HSCs, and this approach could be expanded to test the effect of other selective pressures on both types of HSCs [ 120 , 121 ].…”

Targeted sequencing of candidate gene regions for myelofibrosis in dogs

“…It is hypothesized that chronic bone marrow inflammation attenuates the hematopoietic stem cell progenitor pool over time, because inflammatory cytokine cascades damage and prematurely age progenitor cells, while those with a selective advantage expand to fill the void. 38 , 56 , 57 This phenomenon also could explain the lack of mutations in our healthy control dogs, which had no known hematologic abnormalities. Unfortunately, CBC data was only available from 11 control dogs, and bone marrow samples were not available from any of them to verify the absence of bone marrow pathology.…”