Chronic myelomonocytic leukemia (CMML) is a stem cell-derived neoplasm characterized by dysplasia, uncontrolled expansion of monocytes, and substantial risk to transform to secondary acute myeloid leukemia (sAML). So far, little is known about CMML-initiating cells. We found that leukemic stem cells (LSC) in CMML reside in a CD34+/CD38− fraction of the malignant clone. Whereas CD34+/CD38− cells engrafted NSGS mice with overt CMML, no CMML was produced by CD34+/CD38+ progenitors or the bulk of CD34− monocytes. CMML LSC invariably expressed CD33, CD117, CD123 and CD133. In a subset of patients, CMML LSC also displayed CD52, IL-1RAP and/or CLL-1. CMML LSC did not express CD25 or CD26. However, in sAML following CMML, the LSC also expressed CD25 and high levels of CD114, CD123 and IL-1RAP. No correlations between LSC phenotypes, CMML-variant, mutation-profiles, or clinical course were identified. Pre-incubation of CMML LSC with gemtuzumab-ozogamicin or venetoclax resulted in decreased growth and impaired engraftment in NSGS mice. Together, CMML LSC are CD34+/CD38− cells that express a distinct profile of surface markers and target-antigens. During progression to sAML, LSC acquire or upregulate certain cytokine receptors, including CD25, CD114 and CD123. Characterization of CMML LSC should facilitate their enrichment and the development of LSC-eradicating therapies.
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Storniolo AM, Moloney WC, Rosenthal DS, Cox C, Bennett JM. Chronic myelomonocytic leukemia. Leukemia. 1990;4:766–70.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189–99.
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick H, et al. The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French–American–British cooperative leukaemia group. Br J Haematol. 1994;87:746–54.
Patnaik MM, Parikh SA, Hanson CA, Tefferi A. Chronic myelomonocytic leukaemia: a concise clinical and pathophysiological review. Br J Haematol. 2014;165:273–86.
McCullough KB, Patnaik MM. Chronic myelomonocytic leukemia: a genetic and clinical Update. Curr Hematol Malig Rep. 2015;10:292–302.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Beau MML, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.
Orazi A, Bennett JM, Germing U, Brunning RD, Bain BJ, Cazzola M et al. Chronic myelomonocytic leukaemia. In: WHO classification of tumours of haematopoietic and lymphoid tissues. IARC Press, 2017, pp 82–86.
Kohlmann A, Grossmann V, Klein H-U, Schindela S, Weiss T, Kazak B, et al. Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. J Clin Oncol. 2010;28:3858–65.
Itzykson R, Duchmann M, Lucas N, Solary E. CMML: clinical and molecular aspects. Int J Hematol. 2017;105:711–9.
Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management. Am J Hematol. 2020;95:97–115.
Pich A, Riera L, Sismondi F, Godio L, Davico Bonino L, Marmont F, et al. JAK2V617F activating mutation is associated with the myeloproliferative type of chronic myelomonocytic leukaemia. J Clin Pathol. 2009;62:798–801.
Gur HD, Loghavi S, Garcia-Manero G, Routbort M, Kanagal-Shamanna R, Quesada A, et al. Chronic myelomonocytic leukemia with fibrosis is a distinct disease subset with myeloproliferative features and frequent JAK2 p.V617F mutations. Am J Surg Pathol. 2018;42:799–806.
Sperr WR, Horny H-P, Valent P. Spectrum of associated clonal hematologic non-mast cell lineage disorders occurring in patients with systemic mastocytosis. Int Arch Allergy Immunol. 2002;127:140–2.
Sotlar K, Fridrich C, Mall A, Jaussi R, Bültmann B, Valent P, et al. Detection of c-kit point mutation Asp-816 –> Val in microdissected pooled single mast cells and leukemic cells in a patient with systemic mastocytosis and concomitant chronic myelomonocytic leukemia. Leuk Res. 2002;26:979–84.
Valent P, Orazi A, Savona MR, Patnaik MM, Onida F, van de Loosdrecht AA, et al. Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions. Haematologica. 2019;104:1935–49.
Patnaik MM, Vallapureddy R, Lasho TL, Hoversten KP, Finke CM, Ketterling RP, et al. A comparison of clinical and molecular characteristics of patients with systemic mastocytosis with chronic myelomonocytic leukemia to CMML alone. Leukemia. 2018;32:1850–6.
Itzykson R, Kosmider O, Renneville A, Gelsi-Boyer V, Meggendorfer M, Morabito M, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31:2428–36.
Elena C, Gallì A, Such E, Meggendorfer M, Germing U, Rizzo E, et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood. 2016;128:1408–17.
Palomo L, Garcia O, Arnan M, Xicoy B, Fuster F, Cabezón M, et al. Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features. Oncotarget. 2016;7:57021–35.
Itzykson R, Fenaux P, Bowen D, Cross NCP, Cortes J, De Witte T, et al. Diagnosis and treatment of chronic myelomonocytic leukemias in adults: recommendations from the European hematology association and the European leukemiaNet. Hemasphere. 2018;2:e150.
Kröger N, Zabelina T, Guardiola P, Runde V, Sierra J, Van Biezen A, et al. Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the chronic leukaemia working party of the european group for blood and marrow transplantation (EBMT). Br J Haematol. 2002;118:67–73.
de Witte T, Bowen D, Robin M, Malcovati L, Niederwieser D, Yakoub-Agha I, et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017;129:1753–62.
Dick JE, Lapidot T, Pflumio F. Transplantation of normal and leukemic human bone marrow into immune-deficient mice: development of animal models for human hematopoiesis. Immunol Rev. 1991;124:25–43.
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8.
Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7.
Eisterer W, Jiang X, Christ O, Glimm H, Lee KH, Pang E, et al. Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of the human disease. Leukemia. 2005;19:435–41.
Kavalerchik E, Goff D, Jamieson CHM. Chronic myeloid leukemia stem cells. J Clin Oncol. 2008;26:2911–5.
Krause DS, Van Etten RA. Right on target: eradicating leukemic stem cells. Trends Mol Med. 2007;13:470–81.
Misaghian N, Ligresti G, Steelman LS, Bertrand FE, Bäsecke J, Libra M, et al. Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. Leukemia. 2009;23:25–42.
Copland M. Chronic myelogenous leukemia stem cells: what’s new? Curr Hematol Malig Rep. 2009;4:66–73.
Valent P. Targeting of leukemia-initiating cells to develop curative drug therapies: straightforward but nontrivial concept. Curr Cancer Drug Targets. 2011;11:56–71.
Taussig DC, Miraki-Moud F, Anjos-Afonso F, Pearce DJ, Allen K, Ridler C, et al. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood. 2008;112:568–75.
Jamieson CHM, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004;351:657–67.
Järås M, Johnels P, Hansen N, Agerstam H, Tsapogas P, Rissler M, et al. Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein. Proc Natl Acad Sci USA. 2010;107:16280–5.
Herrmann H, Sadovnik I, Cerny-Reiterer S, Rülicke T, Stefanzl G, Willmann M, et al. Dipeptidylpeptidase IV (CD26) defines leukemic stem cells (LSC) in chronic myeloid leukemia. Blood. 2014;123:3951–62.
Saito Y, Kitamura H, Hijikata A, Tomizawa-Murasawa M, Tanaka S, Takagi S, et al. Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. Sci Transl Med. 2010;2:17ra9–17ra9.
Hosen N, Park CY, Tatsumi N, Oji Y, Sugiyama H, Gramatzki M, et al. CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. Proc Natl Acad Sci USA. 2007;104:11008–13.
van Rhenen A, van Dongen GAMS, Kelder A, Rombouts EJ, Feller N, Moshaver B, et al. The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood. 2007;110:2659–66.
Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138:286–99.
Zhang Y, He L, Selimoglu-Buet D, Jego C, Morabito M, Willekens C, et al. Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines. Blood Adv. 2017;1:972–9.
Yoshimi A, Balasis ME, Vedder A, Feldman K, Ma Y, Zhang H, et al. Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML. Blood. 2017;130:397–407.
Ramshaw HS, Bardy PG, Lee MA, Lopez AF. Chronic myelomonocytic leukemia requires granulocyte-macrophage colony-stimulating factor for growth in vitro and in vivo. Exp Hematol. 2002;30:1124–31.
Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty SV, Teichmann LL, et al. Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol. 2014;32:364–72.
Valent P, Schmidt G, Besemer J, Mayer P, Zenke G, Liehl E, et al. Interleukin-3 is a differentiation factor for human basophils. Blood. 1989;73:1763–9.
Saito H, Hatake K, Dvorak AM, Leiferman KM, Donnenberg AD, Arai N, et al. Selective differentiation and proliferation of hematopoietic cells induced by recombinant human interleukins. PNAS. 1988;85:2288–92.
Sadovnik I, Hoelbl-Kovacic A, Herrmann H, Eisenwort G, Cerny-Reiterer S, Warsch W, et al. Identification of CD25 as STAT5-dependent growth regulator of leukemic stem cells in Ph+ CML. Clin Cancer Res. 2016;22:2051–61.
Hadzijusufovic E, Keller A, Berger D, Greiner G, Wingelhofer B, Witzeneder N, et al. STAT5 is expressed in CD34+/CD38– stem cells and serves as a potential molecular target in Ph-negative myeloproliferative neoplasms. Cancers. 2020;12:1021.
Wingelhofer B, Neubauer HA, Valent P, Han X, Constantinescu SN, Gunning PT, et al. Implications of STAT3 and STAT5 signaling on gene regulation and chromatin remodeling in hematopoietic cancer. Leukemia. 2018;32:1713–26.
Wingelhofer B, Maurer B, Heyes EC, Cumaraswamy AA, Berger-Becvar A, de Araujo ED, et al. Pharmacologic inhibition of STAT5 in acute myeloid leukemia. Leukemia. 2018;32:1135–46.
Müller‐Thomas C, Heider M, Piontek G, Schlensog M, Bassermann F, Kirchner T, et al. Prognostic value of indoleamine 2,3 dioxygenase in patients with higher‐risk myelodysplastic syndromes treated with azacytidine. Br J Haematol. 2020;190:361–70.
Mangaonkar AA, Reichard KK, Binder M, Coltro G, Lasho TL, Carr RM, et al. Bone marrow dendritic cell aggregates associate with systemic immune dysregulation in chronic myelomonocytic leukemia. Blood Adv. 2020;4:5425–30.
Lou Y, Shao L, Mao L, Lu Y, Ma Y, Fan C, et al. Efficacy and predictive factors of venetoclax combined with azacitidine as salvage therapy in advanced acute myeloid leukemia patients: a multicenter retrospective study. Leuk Res. 2020;91:106317.
We like to thank Christiana Winding, Tina Bernthaler, and Siegfried Kosik for skillful technical assistance. This study was supported by the Austrian Science Fund (FWF), grants F4704-B20, P30625-B28, and a Research Grant of the Medical University of Vienna, Austria. Cell sorting experiments were performed with support from the Core Facility Flow Cytometry, Medical University of Vienna.
Conflict of interest
PV received honoraria from Pfizer. HS received honoraria from Pfizer and AbbVie. MD received honoraria from Pfizer and Incyte. The other authors declare no conflict of interest.
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Eisenwort, G., Sadovnik, I., Keller, A. et al. Phenotypic characterization of leukemia-initiating stem cells in chronic myelomonocytic leukemia. Leukemia (2021). https://doi.org/10.1038/s41375-021-01227-z