[en] Telomere length (TL) in peripheral blood (PB) cells of patients with chronic myeloid leukemia (CML) has been shown to correlate with disease stage, prognostic scores, response to therapy, and disease progression. However, due to considerable genetic interindividual variability, TL varies substantially between individuals, limiting its use as a robust prognostic marker in individual patients. Here, we compared TL of BCR-ABL(-), nonleukemic CD34(+)CD38(-) hematopoietic stem cells (HSC) in the bone marrow of CML patients at diagnosis to their individual BCR-ABL(+) leukemic stem cell (LSC) counterparts. We observed significantly accelerated telomere shortening in LSC compared with nonleukemic HSC. Interestingly, the degree of LSC telomere shortening was found to correlate significantly with the leukemic clone size. To validate the diagnostic value of nonleukemic cells as internal controls and to rule out effects of tyrosine kinase inhibitor (TKI) treatment on these nontarget cells, we prospectively assessed TL in 134 PB samples collected in deep molecular remission after TKI treatment within the EURO-SKI study (NCT01596114). Here, no significant telomere shortening was observed in granulocytes compared with an age-adjusted control cohort. In conclusion, this study provides proof of principle for accelerated telomere shortening in LSC as opposed to HSC in CML patients at diagnosis. The fact that the degree of telomere shortening correlates with leukemic clone's size supports the use of TL in leukemic cells as a prognostic parameter pending prospective validation. TL in nonleukemic myeloid cells seems unaffected even by long-term TKI treatment arguing against a reduction of telomere-mediated replicative reserve in normal hematopoiesis under TKI treatment.
Disciplines :
Hematology
Author, co-author :
Bouillon, Anne-Sophie ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'hématologie clinique
Chereda B, Melo JV. Natural course and biology of CML. Ann Hematol. 2015;94(suppl 2):S107-S121.
Alvarez RH, Kantarjian H, Cortes JE. The biology of chronic myelogenous leukemia: implications for imatinib therapy. Semin Hematol. 2007;44(1 suppl 1):S4-S14.
Thielen N, Richter J, Baldauf M, Barbany G, Fioretos T, Giles F, Gjertsen BT, Hochhaus A, et al. Leukemic stem cell quantification in newly diagnosed patients with chronic myeloid leukemia predicts response to nilotinib therapy. Clin Cancer res. 2016;22(16):4030-4038.
Hjorth-Hansen H, Stenke L, Söderlund S, et al; Nordic CML Study Group. Dasatinib induces fast and deep responses in newly diagnosed chronic myeloid leukaemia patients in chronic phase: clinical results from a randomised phase-2 study (NordCML006). Eur J Haematol. 2015;94(3):243-250.
Mustjoki S, Richter J, Barbany G, et al; Nordic CML Study Group (NCMLSG). Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients. Leukemia. 2013;27(7):1520-1526.
Brümmendorf TH, Holyoake TL, Rufer N, et al. Prognostic implications of differences in telomere length between normal and malignant cells from patients with chronic myeloid leukemia measured by flow cytometry. Blood. 2000;95(6):1883-1890.
Boultwood J, Fidler C, Shepherd P, et al. Telomere length shortening is associated with disease evolution in chronic myelogenous leukemia. Am J Hematol. 1999;61(1):5-9.
Brümmendorf TH, Ersöz I, Hartmann U, et al. Telomere length in peripheral blood granulocytes reflects response to treatment with imatinib in patients with chronic myeloid leukemia. Blood. 2003;101(1):375-376.
Drummond M, Lennard A, Brûmmendorf T, Holyoake T. Telomere shortening correlates with prognostic score at diagnosis and proceeds rapidly during progression of chronic myeloid leukemia. Leuk Lymphoma. 2004;45(9):1775-1781.
Hartmann U, Balabanov S, Ziegler P, et al. Telomere length and telomerase activity in the BCR-ABL-transformed murine Pro-B cell line BaF3 is unaffected by treatment with imatinib. Exp Hematol. 2005;33(5):542-549.
Wenn K, Tomala L, Wilop S, et al. Telomere length at diagnosis of chronic phase chronic myeloid leukemia (CML-CP) identifies a subgroup with favourable prognostic parameters and molecular response according to the ELN criteria after 12 months of treatment with nilotinib. Leukemia. 2015; 29(12):2402-2404.
Brümmendorf TH, Balabanov S. Telomere length dynamics in normal hematopoiesis and in disease states characterized by increased stem cell turnover. Leukemia. 2006;20(10):1706-1716.
Rufer N, Brümmendorf TH, Kolvraa S, et al. Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J Exp Med. 1999;190(2):157-167.
Ventura Ferreira MS, Crysandt M, Ziegler P, et al. Evidence for a pre-existing telomere deficit in non-clonal hematopoietic stem cells in patients with acute myeloid leukemia. Ann Hematol. 2017;96(9):1457-1461.
Hummel S, Ventura Ferreira MS, Heudobler D, et al. Telomere shortening in enterocytes of patients with uncontrolled acute intestinal graft-versus-host disease. Blood. 2015;126(22):2518-2521.
Werner B, Beier F, Hummel S, et al. Reconstructing the in vivo dynamics of hematopoietic stem cells from telomere length distributions. eLife. 2015;4:e08687.
Beier F, Masouleh BK, Buesche G, et al. Telomere dynamics in patients with del (5q) MDS before and under treatment with lenalidomide [published online ahead of print 2015 September 2015]. Leuk Res. doi:10.1016/j.leukres.2015.09.003. S0145-2126(15)30380-5.
Schneider RK, Schenone M, Ferreira MV, et al. Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9. Nat Med. 2016;22(3):288-297.
Saussele S, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19(6):747-757.
Sloma I, Jiang X, Eaves AC, Eaves CJ. Insights into the stem cells of chronic myeloid leukemia. Leukemia. 2010;24(11):1823-1833.
Bhatia M, Wang JC, Kapp U, Bonnet D, Dick JE. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci USA. 1997;94(10):5320-5325.
Eisterer W, Jiang X, Christ O, et al. Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of the human disease. Leukemia. 2005;19(3):435-441.
Giustacchini A, Thongjuea S, Barkas N, et al. Single-cell transcriptomics uncovers distinct molecular signatures of stem cells in chronic myeloid leukemia. Nat Med. 2017;23(6):692-702.
Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63(4):789-799.
Hasford J, Pfirrmann M, Hehlmann R, et al; Writing Committee for the Collaborative CML Prognostic Factors Project Group. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst. 1998;90(11):850-858.
Hasford J, Baccarani M, Hoffmann V, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011;118(3):686-692.
Pfirrmann M, Baccarani M, Saussele S, et al. Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia. 2016;30(1):48-56.
Fabarius A, Leitner A, Hochhaus A, et al; Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) and the German CML Study Group. Impact of additional cytogenetic aberrations at diagnosis on prognosis of CML: long-term observation of 1151 patients from the randomized CML Study IV. Blood. 2011;118(26):6760-6768.
Brummendorf TH, Ersoz I, Hartmann U, et al. Normalization of previously shortened telomere length under treatment with imatinib argues against a preexisting telomere length deficit in normal hematopoietic stem cells from patients with chronic myeloid leukemia. Ann N Y Acad Sci. 2003;996:26-38.
Keller G, Brassat U, Braig M, Heim D, Wege H, Brümmendorf TH. Telomeres and telomerase in chronic myeloid leukaemia: impact for pathogenesis, disease progression and targeted therapy. Hematol Oncol. 2009;27(3):123-129.
Ohyashiki K, Iwama H, Tauchi T, et al. Telomere dynamics and genetic instability in disease progression of chronic myeloid leukemia. Leuk Lymphoma. 2000;40(1-2):49-56.
Vajen B, Thomay K, Schlegelberger B. Induction of chromosomal instability via telomere dysfunction and epigenetic alterations in myeloid neoplasia. Cancers (Basel). 2013;5(3):857-874.
Braig M, Pällmann N, Preukschas M, et al. A ‘telomere-associated secretory phenotype’ cooperates with BCR-ABL to drive malignant proliferation of leukemic cells. Leukemia. 2014;28(10):2028-2039.
Brassat U, Balabanov S, Bali D, Dierlamm J, Braig M, Hartmann U, Sirma H, Gunes C, et al. Functional p53 is required for effective execution of telomerase inhibition in BCR-ABL-positive CML cells. Exp Hematol. 2011;39(1):66-76.e1-2.
Baerlocher GM, Vulto I, de Jong G, Lansdorp PM. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat Protoc. 2006; 1(5):2365-2376.
Aubert G, Baerlocher GM, Vulto I, Poon SS, Lansdorp PM. Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes. PLoS Genet. 2012;8(5):e1002696.
Samassekou O, Ntwari A, Hébert J, Yan J. Individual telomere lengths in chronic myeloid leukemia. Neoplasia. 2009;11(11):1146-1154.
Welner RS, Amabile G, Bararia D, et al. Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells. Cancer Cell. 2015;27(5):671-681.
Baerlocher GM, Lansdorp PM. Telomere length measurements in leukocyte subsets by automated multicolor flow-FISH. Cytometry A. 2003;55(1):1-6.
Beier F, Balabanov S, Amberger CC, et al. Telomere length analysis in monocytes and lymphocytes from patients with systemic lupus erythematosus using multi-color flow-FISH. Lupus. 2007;16(12):955-962.
Nieborowska-Skorska M, Kopinski PK, Ray R, et al. Rac2-MRC-cIII-generated ROS cause genomic instability in chronic myeloid leukemia stem cells and primitive progenitors. Blood. 2012;119(18):4253-4263.
Samassekou O, Malina A, Hébert J, Yan J. Presence of alternative lengthening of telomeres associated circular extrachromosome telomere repeats in primary leukemia cells of chronic myeloid leukemia. J Hematol Oncol. 2013;6:26.
Lansdorp PM. Maintenance of telomere length in AML. Blood Adv. 2017;1(25):2467-2472.
Vasko T, Kaifie A, Stope MB, Kraus T, Ziegler P. Telomeres and telomerase in hematopoietic dysfunction: prognostic implications and pharmacological interventions. Int J Mol Sci. 2017;18(11):2267.