Stem Cell Gene Expression Programs Influence Clinical Outcome in Human Leukemia

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2011 Aug 30

PMID 21873988

Citations 557

Authors

Kolja Eppert

Katsuto Takenaka

Eric R Lechman

Levi Waldron

Bjorn Nilsson

Peter van Galen

Klaus H Metzeler

Armando Poeppl

Vicki Ling

Joseph Beyene

Angelo J Canty

Jayne S Danska

Stefan K Bohlander

Christian Buske

Mark D Minden

Todd R Golub

Igor Jurisica

Benjamin L Ebert

John E Dick

Affiliations

Soon will be listed here.

Abstract

Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying 'stemness' properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.

Citing Articles

Overexpression of miR-99a promoted expansion and suppressed differentiation of hematopoietic stem/progenitor cells.

Wang W, Hao X, Lv X, Li Y, Xing W, Chen T Sci Rep. 2025; 15(1):8890.

PMID: 40087327 DOI: 10.1038/s41598-025-92827-7.

Continuous map of early hematopoietic stem cell differentiation across human lifetime.

Komic H, Schmachtel T, Simoes C, Kulp M, Yu W, Jolly A Nat Commun. 2025; 16(1):2287.

PMID: 40055319 PMC: 11889232. DOI: 10.1038/s41467-025-57096-y.

Inhibition of the STAT3/Fanconi anemia axis is synthetic lethal with PARP inhibition in breast cancer.

Rouault C, Bansard L, Martinez-Balsalobre E, Bonnet C, Wicinski J, Lin S Nat Commun. 2025; 16(1):2159.

PMID: 40038300 PMC: 11880418. DOI: 10.1038/s41467-025-57476-4.

Distinct leukemogenic mechanism of acute promyelocytic leukemia based on genomic structure of PML::RARα.

Minami M, Sakoda T, Kawano G, Kochi Y, Sasaki K, Sugio T Leukemia. 2025; .

PMID: 39979604 DOI: 10.1038/s41375-025-02530-9.

Effective eradication of acute myeloid leukemia stem cells with FLT3-directed antibody-drug conjugates.

Able M, Kasper M, Vick B, Schwach J, Gao X, Schmitt S Leukemia. 2025; 39(3):632-642.

PMID: 39870768 PMC: 11879846. DOI: 10.1038/s41375-024-02510-5.

References

Guzman M, Upchurch D, Grimes B, Howard D, Rizzieri D, Luger S . Expression of tumor-suppressor genes interferon regulatory factor 1 and death-associated protein kinase in primitive acute myelogenous leukemia cells. Blood. 2001; 97(7):2177-9. DOI: 10.1182/blood.v97.7.2177. View

Oh I, Eaves C . Overexpression of a dominant negative form of STAT3 selectively impairs hematopoietic stem cell activity. Oncogene. 2002; 21(31):4778-87. DOI: 10.1038/sj.onc.1205592. View

Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick J . Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011; 333(6039):218-21. DOI: 10.1126/science.1201219. View

Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S . Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007; 25(11):1315-21. DOI: 10.1038/nbt1350. View

Brown K, Jurisica I . Online predicted human interaction database. Bioinformatics. 2005; 21(9):2076-82. DOI: 10.1093/bioinformatics/bti273. View

Bjornsson J, Larsson N, Brun A, Magnusson M, Andersson E, Lundstrom P . Reduced proliferative capacity of hematopoietic stem cells deficient in Hoxb3 and Hoxb4. Mol Cell Biol. 2003; 23(11):3872-83. PMC: 155209. DOI: 10.1128/MCB.23.11.3872-3883.2003. View

Guzman M, Neering S, Upchurch D, Grimes B, Howard D, Rizzieri D . Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001; 98(8):2301-7. DOI: 10.1182/blood.v98.8.2301. View

Bao S, Wu Q, McLendon R, Hao Y, Shi Q, Hjelmeland A . Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006; 444(7120):756-60. DOI: 10.1038/nature05236. View

Gentles A, Plevritis S, Majeti R, Alizadeh A . Association of a leukemic stem cell gene expression signature with clinical outcomes in acute myeloid leukemia. JAMA. 2010; 304(24):2706-15. PMC: 4089862. DOI: 10.1001/jama.2010.1862. View

10.

Hu Y, Smyth G . ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2009; 347(1-2):70-8. DOI: 10.1016/j.jim.2009.06.008. View

11.

Taussig D, Miraki-Moud F, Anjos-Afonso F, Pearce D, Allen K, Ridler C . Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood. 2008; 112(3):568-75. DOI: 10.1182/blood-2007-10-118331. View

12.

Quintana E, Shackleton M, Sabel M, Fullen D, Johnson T, Morrison S . Efficient tumour formation by single human melanoma cells. Nature. 2008; 456(7222):593-8. PMC: 2597380. DOI: 10.1038/nature07567. View

13.

McDermott S, Eppert K, Lechman E, Doedens M, Dick J . Comparison of human cord blood engraftment between immunocompromised mouse strains. Blood. 2010; 116(2):193-200. DOI: 10.1182/blood-2010-02-271841. View

14.

Adams J, Strasser A . Is tumor growth sustained by rare cancer stem cells or dominant clones?. Cancer Res. 2008; 68(11):4018-21. DOI: 10.1158/0008-5472.CAN-07-6334. View

15.

Taussig D, Vargaftig J, Miraki-Moud F, Griessinger E, Sharrock K, Luke T . Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(-) fraction. Blood. 2010; 115(10):1976-84. PMC: 2837317. DOI: 10.1182/blood-2009-02-206565. View

16.

Schnittger S, Schoch C, Kern W, Mecucci C, Tschulik C, Martelli M . Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood. 2005; 106(12):3733-9. DOI: 10.1182/blood-2005-06-2248. View

17.

Radmacher M, Marcucci G, Ruppert A, Mrozek K, Whitman S, Vardiman J . Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study. Blood. 2006; 108(5):1677-83. PMC: 1895508. DOI: 10.1182/blood-2006-02-005538. View

18.

Li X, Lewis M, Huang J, Gutierrez C, Osborne C, Wu M . Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008; 100(9):672-9. DOI: 10.1093/jnci/djn123. View

19.

Metzeler K, Hummel M, Bloomfield C, Spiekermann K, Braess J, Sauerland M . An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia. Blood. 2008; 112(10):4193-201. PMC: 2954679. DOI: 10.1182/blood-2008-02-134411. View

20.

Karanu F, Murdoch B, Gallacher L, Wu D, Koremoto M, Sakano S . The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med. 2000; 192(9):1365-72. PMC: 2193352. DOI: 10.1084/jem.192.9.1365. View