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Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion

Authors: Kerstin Cornils, Lars Thielecke, Doreen Winkelmann, Tim Aranyossy, Mathias Lesche, Andreas Dahl, Ingo Roeder, Boris Fehse, Ingmar Glauche

Published in: Molecular Cancer | Issue 1/2017

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Abstract

Background

Clonal competition in cancer describes the process in which the progeny of a cell clone supersedes or succumbs to other competing clones due to differences in their functional characteristics, mostly based on subsequently acquired mutations. Even though the patterns of those mutations are well explored in many tumors, the dynamical process of clonal selection is underexposed.

Methods

We studied the dynamics of clonal competition in a BcrAbl-induced leukemia using a γ-retroviral vector library encoding the oncogene in conjunction with genetic barcodes. To this end, we studied the growth dynamics of transduced cells on the clonal level both in vitro and in vivo in transplanted mice.

Results

While we detected moderate changes in clonal abundancies in vitro, we observed monoclonal leukemias in 6/30 mice after transplantation, which intriguingly were caused by only two different BcrAbl clones. To analyze the success of these clones, we applied a mathematical model of hematopoietic tissue maintenance, which indicated that a differential engraftment capacity of these two dominant clones provides a possible explanation of our observations. These findings were further supported by additional transplantation experiments and increased BcrAbl transcript levels in both clones.

Conclusion

Our findings show that clonal competition is not an absolute process based on mutations, but highly dependent on selection mechanisms in a given environmental context.
Appendix
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Literature
1.
2.
Kumar R, Li DQ, Muller S, Knapp S. Epigenomic regulation of oncogenesis by chromatin remodeling. Oncogene. 2016;35(34):4423–36.CrossRefPubMed
3.
4.
Schepers K, Campbell TB, Passegue E. Normal and leukemic stem cell niches: insights and therapeutic opportunities. Cell Stem Cell. 2015;16(3):254–67.CrossRefPubMedPubMedCentral
5.
6.
Caiado F, Silva-Santos B, Norell H. Intra-tumour heterogeneity - going beyond genetics. Febs J. 2016;283(12):2245–58.CrossRefPubMed
7.
Kustikova OS, Schiedlmeier B, Brugman MH, Stahlhut M, Bartels S, Li Z, et al. Cell-intrinsic and vector-related properties cooperate to determine the incidence and consequences of insertional mutagenesis. Mol Ther. 2009;17(9):1537–47.CrossRefPubMedPubMedCentral
8.
Cornils K, Bartholomae CC, Thielecke L, Lange C, Arens A, Glauche I, et al. Comparative clonal analysis of reconstitution kinetics after transplantation of hematopoietic stem cells gene marked with a lentiviral SIN or a gamma-retroviral LTR vector. Exp Hematol. 2013;41(1):28–38. e3CrossRefPubMed
9.
Biasco L, Pellin D, Scala S, Dionisio F, Basso-Ricci L, Leonardelli L, et al. In vivo tracking of human Hematopoiesis reveals patterns of clonal dynamics during early and steady-state reconstitution phases. Cell Stem Cell. 2016;19(1):107–19.CrossRefPubMedPubMedCentral
10.
Schepers K, Swart E, van Heijst JW, Gerlach C, Castrucci M, Sie D, et al. Dissecting T cell lineage relationships by cellular barcoding. J Exp Med. 2008;205(10):2309–18.CrossRefPubMedPubMedCentral
11.
Gerrits A, Dykstra B, Kalmykowa OJ, Klauke K, Verovskaya E, Broekhuis MJ, et al. Cellular barcoding tool for clonal analysis in the hematopoietic system. Blood. 2010;115(13):2610–8.CrossRefPubMed
12.
Naik SH, Perie L, Swart E, Gerlach C, van Rooij N, de Boer RJ, et al. Diverse and heritable lineage imprinting of early haematopoietic progenitors. Nature. 2013;496(7444):229–32.CrossRefPubMed
13.
Bhang HE, Ruddy DA, Krishnamurthy Radhakrishna V, Caushi JX, Zhao R, Hims MM, et al. Studying clonal dynamics in response to cancer therapy using high-complexity barcoding. Nat Med. 2015;21(5):440–8.CrossRefPubMed
14.
Cornils K, Thielecke L, Huser S, Forgber M, Thomaschewski M, Kleist N, et al. Multiplexing clonality: combining RGB marking and genetic barcoding. Nucleic Acids Res. 2014;42(7):e56.CrossRefPubMedPubMedCentral
15.
Klauke K, Broekhuis MJ, Weersing E, Dethmers-Ausema A, Ritsema M, Gonzalez MV, et al. Tracing dynamics and clonal heterogeneity of Cbx7-induced leukemic stem cells by cellular barcoding. Stem Cell Rep. 2015;4(1):74–89.CrossRef
16.
Melo JV, Barnes DJ. Chronic myeloid leukaemia as a model of disease evolution in human cancer. Nat Rev Cancer. 2007;7(6):441–53.CrossRefPubMed
17.
McLaughlin J, Chianese E, Witte ON. In vitro transformation of immature hematopoietic cells by the P210 BCR/ABL oncogene product of the Philadelphia chromosome. Proc Natl Acad Sci U S A. 1987;84(18):6558–62.CrossRefPubMedPubMedCentral
18.
Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science. 1990;247(4944):824–30.CrossRefPubMed
19.
Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5(3):172–83.CrossRefPubMed
20.
Braig M, Pallmann N, Preukschas M, Steinemann D, Hofmann W, Gompf A, et al. A ‘telomere-associated secretory phenotype’ cooperates with BCR-ABL to drive malignant proliferation of leukemic cells. Leukemia. 2014;28(10):2028–39.CrossRefPubMed
21.
Hildinger M, Abel KL, Ostertag W, Baum C. Design of 5′ untranslated sequences in retroviral vectors developed for medical use. J Virol. 1999;73(5):4083–9.PubMedPubMedCentral
22.
Newrzela S, Cornils K, Li Z, Baum C, Brugman MH, Hartmann M, et al. Resistance of mature T cells to oncogene transformation. Blood. 2008;112(6):2278–86.CrossRefPubMed
23.
Thielecke L, Aranyossy T, Dahl A, Tiwari R, Roeder I, Geiger H, et al. Limitations and challenges of genetic barcode quantification. Sci Rep. 2017;7:43249.CrossRefPubMedPubMedCentral
24.
Gibson DG, Young L, Chuang RY, Venter JC, Hutchison CA 3rd, Smith HO. Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat Methods. 2009;6(5):343–5.CrossRefPubMed
25.
Cornils K, Lange C, Schambach A, Brugman MH, Nowak R, Lioznov M, et al. Stem cell marking with promotor-deprived self-inactivating retroviral vectors does not lead to induced clonal imbalance. Mol Ther. 2009;17(1):131–43.CrossRefPubMed
26.
Palacios R, Steinmetz M. Il-3-dependent mouse clones that express B-220 surface antigen, contain Ig genes in germ-line configuration, and generate B lymphocytes in vivo. Cell. 1985;41(3):727–34.CrossRefPubMed
27.
Daley GQ, Baltimore D. Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. Proc Natl Acad Sci U S A. 1988;85(23):9312–6.CrossRefPubMedPubMedCentral
28.
Kustikova OS, Baum C, Fehse B. Retroviral integration site analysis in hematopoietic stem cells. Methods Mol Biol. 2008;430:255–67.CrossRefPubMed
29.
Huston MW, Brugman MH, Horsman S, Stubbs A, van der Spek P, Wagemaker G. Comprehensive investigation of parameter choice in viral integration site analysis and its effects on the gene annotations produced. Hum Gene Ther. 2012;23(11):1209–19.CrossRefPubMed
30.
Gabert J, Beillard E, van der Velden VH, Bi W, Grimwade D, Pallisgaard N, et al. Standardization and quality control studies of ‘real-time’ quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia - a Europe against cancer program. Leukemia. 2003;17(12):2318–57.CrossRefPubMed
31.
32.
Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30(7):923–30.CrossRefPubMed
33.
34.
35.
Roeder I, Loeffler M. A novel dynamic model of hematopoietic stem cell organization based on the concept of within-tissue plasticity. Exp Hematol. 2002;30(8):853–61.CrossRefPubMed
36.
Roeder I, Kamminga LM, Braesel K, Dontje B, de Haan G, Loeffler M. Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization. Blood. 2005;105(2):609–16.CrossRefPubMed
37.
Roeder I, Horn M, Glauche I, Hochhaus A, Mueller MC, Loeffler M. Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nat Med. 2006;12(10):1181–4.CrossRefPubMed
38.
Glauche I, Moore K, Thielecke L, Horn K, Loeffler M, Roeder I. Stem cell proliferation and quiescence--two sides of the same coin. PLoS Comput Biol. 2009;5(7):e1000447.CrossRefPubMedPubMedCentral
39.
Horn M, Glauche I, Muller MC, Hehlmann R, Hochhaus A, Loeffler M, et al. Model-based decision rules reduce the risk of molecular relapse after cessation of tyrosine kinase inhibitor therapy in chronic myeloid leukemia. Blood. 2013;121(2):378–84.CrossRefPubMed
40.
Barnes DJ, Schultheis B, Adedeji S, Melo JV. Dose-dependent effects of Bcr-Abl in cell line models of different stages of chronic myeloid leukemia. Oncogene. 2005;24(42):6432–40.PubMed
41.
42.
43.
Horn M, Loeffler M, Roeder I. Mathematical modeling of genesis and treatment of chronic myeloid leukemia. Cells Tissues Organs. 2008;188(1–2):236–47.CrossRefPubMed
44.
Porter SN, Baker LC, Mittelman D, Porteus MH. Lentiviral and targeted cellular barcoding reveals ongoing clonal dynamics of cell lines in vitro and in vivo. Genome Biol. 2014;15(5):R75.CrossRefPubMedPubMedCentral
45.
Elmaagacli AH, Beelen DW, Opalka B, Seeber S, Schaefer UW. The amount of BCR-ABL fusion transcripts detected by the real-time quantitative polymerase chain reaction method in patients with Philadelphia chromosome positive chronic myeloid leukemia correlates with the disease stage. Ann Hematol. 2000;79(8):424–31.CrossRefPubMed
46.
Hamdane M, David-Cordonnier MH, D'Halluin JC. Activation of p65 NF-kappaB protein by p210BCR-ABL in a myeloid cell line (P210BCR-ABL activates p65 NF-kappaB). Oncogene. 1997;15(19):2267–75.CrossRefPubMed
47.
Reuther JY, Reuther GW, Cortez D, Pendergast AM, Baldwin AS Jr. A requirement for NF-kappaB activation in Bcr-Abl-mediated transformation. Genes dev. 1998;12(7):968–81.CrossRefPubMedPubMedCentral
48.
Kirchner D, Duyster J, Ottmann O, Schmid RM, Bergmann L, Munzert G. Mechanisms of Bcr-Abl-mediated NF-kappaB/Rel activation. Exp Hematol. 2003;31(6):504–11.CrossRefPubMed
49.
Zhao C, Xiu Y, Ashton J, Xing L, Morita Y, Jordan CT, et al. Noncanonical NF-kappaB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions. Stem Cells. 2012;30(4):709–18.CrossRefPubMedPubMedCentral
50.
Stein SJ, Baldwin AS. Deletion of the NF-kappaB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function. Blood. 2013;121(25):5015–24.CrossRefPubMedPubMedCentral
51.
Krause DS, Lazarides K, von Andrian UH, Van Etten RA. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat Med. 2006;12(10):1175–80.CrossRefPubMed
52.
Krause DS, Lazarides K, Lewis JB, von Andrian UH, Van Etten RA. Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche. Blood. 2014;123(9):1361–71.CrossRefPubMedPubMedCentral
53.
Kustikova OS, Wahlers A, Kuhlcke K, Stahle B, Zander AR, Baum C, et al. Dose finding with retroviral vectors: correlation of retroviral vector copy numbers in single cells with gene transfer efficiency in a cell population. Blood. 2003;102(12):3934–7.CrossRefPubMed
54.
Spielmann M, Mundlos S. Structural variations, the regulatory landscape of the genome and their alteration in human disease. BioEssays. 2013;35(6):533–43.CrossRefPubMed
55.
Jiang X, Lopez A, Holyoake T, Eaves A, Eaves C. Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 1999;96(22):12804–9.CrossRefPubMedPubMedCentral
56.
Jiang X, Ng E, Yip C, Eisterer W, Chalandon Y, Stuible M, et al. Primitive interleukin 3 null hematopoietic cells transduced with BCR-ABL show accelerated loss after culture of factor-independence in vitro and leukemogenic activity in vivo. Blood. 2002;100(10):3731–40.CrossRefPubMed
Metadata
Title
Clonal competition in BcrAbl-driven leukemia: how transplantations can accelerate clonal conversion
Authors
Kerstin Cornils
Lars Thielecke
Doreen Winkelmann
Tim Aranyossy
Mathias Lesche
Andreas Dahl
Ingo Roeder
Boris Fehse
Ingmar Glauche
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0668-x

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