Research article Special Issues

Dynamics of competing heterogeneous clones in blood cancers explains multiple observations - a mathematical modeling approach

  • Received: 29 June 2020 Accepted: 11 October 2020 Published: 04 November 2020
  • Heterogeneity of stem cell clones provide a key ingredient in altered hematopoiesis and is of main interest in the study of predisease states as well as in the development of blood cancers such as chronic myeloid leukemia (CML) and the Philadelphia-negative myeloprofilerative neoplasms (MPNs). A mathematical model based on biological mechanisms and basic cell descriptors such as proliferation rates and apoptosis rates is suggested, connecting stem cell dynamics with mature blood cells and immune mediated feedback. The flexible approach allows for arbitrary numbers of mutated stem cell clones with perturbed properties. In particular, the stem cell niche provides a competition between wild type and mutated stem cells. Hence, the stem cell niche can mediate suppression of the wild type clones and up-regulation of one or more malignant clones. The model is parameterized using clinical data to show typical disease progression in several blood cancers and the hematological and molecular response to treatment. Intriguingly, occasional oscillatory cell counts observed during treatment of CML and MPNs can be explained by heterogeneous stem cell clone dynamics. Thus, the vital heterogeneous stem cell dynamics may be inferred from mathematical modeling in synergy with clinical data to elucidate hematopoiesis, blood cancers and the outcome of interventions.

    Citation: Katrine O. Bangsgaard, Morten Andersen, Vibe Skov, Lasse Kjær, Hans C. Hasselbalch, Johnny T. Ottesen. Dynamics of competing heterogeneous clones in blood cancers explains multiple observations - a mathematical modeling approach[J]. Mathematical Biosciences and Engineering, 2020, 17(6): 7645-7670. doi: 10.3934/mbe.2020389

    Related Papers:

  • Heterogeneity of stem cell clones provide a key ingredient in altered hematopoiesis and is of main interest in the study of predisease states as well as in the development of blood cancers such as chronic myeloid leukemia (CML) and the Philadelphia-negative myeloprofilerative neoplasms (MPNs). A mathematical model based on biological mechanisms and basic cell descriptors such as proliferation rates and apoptosis rates is suggested, connecting stem cell dynamics with mature blood cells and immune mediated feedback. The flexible approach allows for arbitrary numbers of mutated stem cell clones with perturbed properties. In particular, the stem cell niche provides a competition between wild type and mutated stem cells. Hence, the stem cell niche can mediate suppression of the wild type clones and up-regulation of one or more malignant clones. The model is parameterized using clinical data to show typical disease progression in several blood cancers and the hematological and molecular response to treatment. Intriguingly, occasional oscillatory cell counts observed during treatment of CML and MPNs can be explained by heterogeneous stem cell clone dynamics. Thus, the vital heterogeneous stem cell dynamics may be inferred from mathematical modeling in synergy with clinical data to elucidate hematopoiesis, blood cancers and the outcome of interventions.


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    [1] S. H. Orkin, L. I. Zon, Hematopoiesis: An evolving paradigm for stem cell biology, Cell, 132 (2008), 631-644. doi: 10.1016/j.cell.2008.01.025
    [2] S. N. Catlin, L. Busque, R. E. Gale, P. Guttorp, J. L. Abkowitz, The replication rate of human hematopoietic stem cells in vivo, Blood, 117 (2011), 4460-4466. doi: 10.1182/blood-2010-08-303537
    [3] H. Lee-Six, N. F. Øbro, M. S. Shepherd, S. Grossmann, K. Dawson, M. Belmonte, et al., Population dynamics of normal human blood inferred from somatic mutations, Nature, 561 (2018), 473-478. doi: 10.1038/s41586-018-0497-0
    [4] D. Dingli, A. Traulsen, J. M. Pacheco, Compartmental architecture and dynamics of hematopoiesis (architecture of hematopoiesis), PLoS ONE, 2 (2007), e345.
    [5] H. Vaziri, W. Dragowska, R. C. Allsopp, T. E. Thomas, C. B. Harley, P. M. Lansdorp, Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age, Proc. Natl. Sci. Acad., 91 (1994), 9857-9860. doi: 10.1073/pnas.91.21.9857
    [6] S. Y. Chen, Y. C. Huang, S. P. Liu, F. J. Tsai, W. C. Shyu, S. Z. Lin, An overview of concepts for cancer stem cells, Cell Trans., 20 (2011), 113-120. doi: 10.3727/096368910X532837
    [7] A. Tefferi, P. Guglielmelli, D. R. Larson, C. Finke, E. A. Wassie, L. Pieri, et al., Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis, Blood, 124 (2014), 2507-2513.
    [8] J. M. Shammo, B. L. Stein, Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions, Hematology, 2016 (2016), 552-560.
    [9] P. J. Campbell, A. R. Green, The myeloproliferative disorders, N. Engl. J. Med., 355 (2006), 2452-2466. doi: 10.1056/NEJMra063728
    [10] L. A. Anderson, M. F. McMullin, Epidemiology of MPN: What do we know?, Curr. Hematol. Malig. Rep., 9 (2014), 340-349. doi: 10.1007/s11899-014-0228-z
    [11] H. C. Hasselbalch, M. E. Bjørn, MPNs as inflammatory diseases: The evidence, consequences, and perspectives, Mediators Inflammation, 2015 (2015), 1-16.
    [12] S. Y. Kristinsson, O. Landgren, J. Samuelsson, M. Bjorkholm, L. R. Goldin, Autoimmunity and the risk of myeloproliferative neoplasms, Haematologica, 95 (2010), 1216-1220. doi: 10.3324/haematol.2009.020412
    [13] R. Marchioli, G. Finazzi, R. Landolfi, J. Kutti, H. Gisslinger, C. Patrono, et al., Vascular and neoplastic risk in a large cohort of patients with polycythemia vera, J. Clin. Onco., 23 (2005), 2224-2232. doi: 10.1200/JCO.2005.07.062
    [14] G. Multhoff, M. Molls, J. Radons, Chronic inflammation in cancer development, Front. Immunol., 2 (2012).
    [15] J. Todoric, L. Antonucci, M. Karin, Targeting inflammation in cancer prevention and therapy, Cancer Prev. Res., 9 (2016), 895-905. doi: 10.1158/1940-6207.CAPR-16-0209
    [16] G. J. Titmarsh, A. S. Duncombe, M. F. McMullin, M. O'Rorke, R. Mesa, F. D. Vocht, et al., How common are myeloproliferative neoplasms? A systematic review and meta-analysis, Am. J. Hematol., 89 (2014), 581-587. doi: 10.1002/ajh.23690
    [17] M. Andersen, Z. Sajid, R. K. Pedersen, J. Gudmand-Hoeyer, C. Ellervik, V. Skov, et al., Mathematical modelling as a proof of concept for MPNs as a human inflammation model for cancer development, PLOS ONE, 12 (2017), e0183620.
    [18] Z. Sajid, M. Andersen, J. T. Ottesen, Mathematical analysis of the cancitis model and the role of inflammation in blood cancer progression, Math. Biosci. Eng., 16 (2019), 8268-8289. doi: 10.3934/mbe.2019418
    [19] M. Andersen, H. Hasselbalch, L. Kjær, V. Skov, J. Ottesen, Global dynamics of healthy and cancer cells competing in the hematopoietic system, Math. Biosci., 2020 (2020), 108372.
    [20] J. T. Ottesen, R. K. Pedersen, Z. Sajid, J. Gudmand-Hoeyer, K. O. Bangsgaard, V. Skov, et al., Bridging blood cancers and inflammation: The reduced cancitis model, J. Theor. Biol., 465 (2019), 90-108. doi: 10.1016/j.jtbi.2019.01.001
    [21] J. Ottesen, R. Pedersen, M. Dam, T. Knudsen, V. Skov, L. Kjær, et al., Mathematical modeling of MPNs offers understanding and decision support for personalized treatment, Cancers, 12 (2020), 2119. doi: 10.3390/cancers12082119
    [22] B. J. Kennedy, Cyclic leukocyte oscillations in chronic myelogenous leukemia during hydroxyurea therapy, Blood, 35 (1970), 751-760. doi: 10.1182/blood.V35.6.751.751
    [23] G. Chikkappa, G. Borner, H. Burlington, A. Chanana, E. Cronkite, S. Ohl, et al., Periodic oscillation of blood leukocytes, platelets, and reticulocytes in a patient with chronic myelocytic leukemia, Blood, 47 (1976), 1023-1030. doi: 10.1182/blood.V47.6.1023.1023
    [24] P. Fortin, M. C. Mackey, Periodic chronic myelogenous leukaemia: spectral analysis of blood cell counts and aetiological implications, Br. J. Haematol., 104 (1999), 336-345. doi: 10.1046/j.1365-2141.1999.01168.x
    [25] Y. Hirayama, S. Sakamaki, Y. Tsuji, T. Matsunaga, Y. Niitsu, Cyclic platelet and leukocyte count oscillation in chronic myelocytic leukemia regulated by the negative feedback of transforming growth factor beta, Int. J. Hematol., 77 (2003), 71-74. doi: 10.1007/BF02982605
    [26] A. Besse, G. D. Clapp, S. Bernard, F. E. Nicolini, D. Levy, T. Lepoutre, Stability analysis of a model of interaction between the immune system and cancer cells in chronic myelogenous leukemia, Bull. Math. Biol., 80 (2017), 1084-1110.
    [27] G. D. Clapp, T. Lepoutre, R. E. Cheikh, S. Bernard, J. Ruby, H. Labussiere-Wallet, et al., Implication of the autologous immune system in BCR-ABL transcript variations in chronic myelogenous leukemia patients treated with imatinib, Cancer Res., 75 (2015), 4053-4062. doi: 10.1158/0008-5472.CAN-15-0611
    [28] F. Knauer, T. Stiehl, A. Marciniak-Czochra, Oscillations in a white blood cell production model with multiple differentiation stages, J. Math. Biol., 80 (2020), 575-600.
    [29] J. H. Baird, C. P. Minniti, J.-M. Lee, X. Tian, C. Wu, M. Jackson, et al., Oscillatory haematopoiesis in adults with sickle cell disease treated with hydroxycarbamide, Br. J. Hematol., 168 (2014), 737-746.
    [30] J. Tauscher, F. Siegel, P. E. Petrides, Hydroxyurea induced oscillations in twelve patients with polycythemia vera, Haematologica, 95 (2010), 1227-1229. doi: 10.3324/haematol.2010.022178
    [31] A. Tefferi, M. A. Elliott, P. C. Kao, S. Yoon, I. El-Hemaidi, T. C. Pearson, Hydroxyurea-induced marked oscillations of platelet counts in patients with polycythemia vera, Blood, 96 (2000), 1582-1584. doi: 10.1182/blood.V96.4.1582
    [32] S. Jaiswal, P. Fontanillas, J. Flannick, A. Manning, P. V. Grauman, B. G. Mar, et al., Age-related clonal hematopoiesis associated with adverse outcomes, N. Engl. J. Med., 371 (2014), 2488-2498. doi: 10.1056/NEJMoa1408617
    [33] M. Heuser, F. Thol, A. Ganser, Clonal hematopoiesis of indeterminate potential, Dtsch. Ärzteblatt Int., 113 (2016), 317.
    [34] D. S. Park, A. A. Akuffo, D. E. Muench, H. L. Grimes, P. K. Epling-Burnette, P. K. Maini, et al., Clonal hematopoiesis of indeterminate potential and its impact on patient trajectories after stem cell transplantation, PLoS Comput. Biol., 15 (2019), e1006913.
    [35] J. Cortes, M. O'Dwyer, Clonal evolution in chronic myelogenous leukemia, Haematol./Oncol. Clin. North Am., 18 (2004), 671-684.
    [36] A. Schuh, J. Becq, S. Humphray, A. Alexa, A. Burns, R. Clifford, et al., Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns, Blood, 120 (2012), 4191-4196.
    [37] M. J. Walter, D. Shen, L. Ding, J. Shao, D. C. Koboldt, K. Chen, et al., Clonal architecture of secondary acute myeloid leukemia, N. Engl. J. Med., 366 (2012), 1090-1098. doi: 10.1056/NEJMoa1106968
    [38] L. Ding, T. J. Ley, D. E. Larson, C. A. Miller, D. C. Koboldt, J. S. Welch, et al., Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing, Nature, 481 (2012), 506-510. doi: 10.1038/nature10738
    [39] K. H. Allison, G. W. Sledge, Heterogeneity and cancer, Oncology, 28 (2014), A11.
    [40] T. Stiehl, N. Baran, A. D. Ho, A. Marciniak-Czochra, Clonal selection and therapy resistance in acute leukaemias: mathematical modelling explains different proliferation patterns at diagnosis and relapse, J. R. Soc. Interface, 11 (2014), 20140079.
    [41] G. P. Dunn, L. J. Old, R. D. Schreiber, The three es of cancer immunoediting, Ann. Rev. Immunol., 22 (2004), 329-360. doi: 10.1146/annurev.immunol.22.012703.104803
    [42] R. J. Jones, S. A. Armstrong, Cancer stem cells in hematopoietic malignancies, Biol. Blood Marrow Trans., 14 (2008), 12-16.
    [43] A. J. Mead, A. Mullally, Myeloproliferative neoplasm stem cells, Blood, 129 (2017), 1607-1616. doi: 10.1182/blood-2016-10-696005
    [44] B. Craver, K. Alaoui, R. Scherber, A. Fleischman, The critical role of inflammation in the pathogenesis and progression of myeloid malignancies, Cancers, 10 (2018), 2-18.
    [45] L. Shlush, A. Mitchell, L. Heisler, S. Abelson, A. Trotman-Grant, J. Medeiros, et al., Tracing the origins of relapse in acute mueloid leukemia to stem cells, Nature, 547 (2017), 104-108. doi: 10.1038/nature22993
    [46] B. Jonas, On the origin of relapse in AML, Sci. Transl. Med., 9(398) (2017), 1-2.
    [47] B. Jonas, Stem cells make leukemia grow again, EMBO J., 36(18) (2017), 2667-2669.
    [48] L. MacPherson, M. Dawson, Survival of the fittest: Darwinian selection underpines chemotherapy resistance in AML, Cell Stem Cell, 21 (2017), 291-292. doi: 10.1016/j.stem.2017.08.004
    [49] J. Hofbauer, J.-H. So, Multiple limit cycles for three dimensional Lotka-Volterra equations, Appl. Math. Lett., 7 (1994), 65-70.
    [50] M. L. Zeeman, Hopf bifurcations in competitive three-dimensional Lotka-Volterra systems, Dyn. Stab. Syst., 8 (1993), 189-216.
    [51] M. L. Zeeman, P. Van Den Driessche, Three-dimensional competitive Lotka-Volterra systems with no periodic orbits, SIAM J. Appl. Math., 58 (1998), 227-234.
    [52] R. M. May, W. J. Leonard, Nonlinear aspects of competition between three species, SIAM J. Appl. Math., 29 (1975), 243-253. doi: 10.1137/0129022
    [53] M. E. Gilpin, Limit cycles in competition communities, Am. Nat., 109 (1975), 51-60. doi: 10.1086/282973
    [54] J. Huisman, F. J. Weissing, Biological conditions for oscillations and chaos generated by multi-species competition, Ecology, 82 (2001), 2682-2695. doi: 10.1890/0012-9658(2001)082[2682:BCFOAC]2.0.CO;2
    [55] J. D. Murray, Interdisciplinary applied mathematics, in Mathematical biology, 3rd edition, Springer, New York, 2003.
    [56] R. K. Pedersen, T. A. Knudsen, Z. Sajid, J. Gudmand-Hoeyer, V. Skov, L. Kjær, et al., Data-driven analysis of JAK2V617F kinetics during interferon-alpha2 treatment of patients with polycythemia vera and related neoplasms, Cancer Med., 9 (2020), 2039-2051. doi: 10.1002/cam4.2741
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