High Frequencies of Leukemia Stem Cells in Poor-outcome Childhood Precursor-B Acute Lymphoblastic Leukemias

Overview

Journal Leukemia

Specialties Hematology
Oncology

Date 2010 Aug 27

PMID 20739953

Citations 25

Authors

S Morisot

A S Wayne

O Bohana-Kashtan

I M Kaplan

C D Gocke

R Hildreth

M Stetler-Stevenson

R L Walker

S Davis

P S Meltzer

S J Wheelan

P Brown

R J Jones

L D Shultz

C I Civin

Affiliations

Soon will be listed here.

Abstract

In order to develop a xenograft model to determine the efficacy of new therapies against primary human precursor-B acute lymphoblastic leukemia (ALL) stem cells (LSCs), we used the highly immunodeficient non-obese diabetic (NOD).Cg-Prkdc(scid)IL2rg(tmlWjl)/SzJ (NOD-severe combined immune deficient (scid) IL2rg(-/-)) mouse strain. Intravenous transplantation of 2 of 2 ALL cell lines and 9 of 14 primary ALL cases generated leukemia-like proliferations in recipient mice by 1-7 months after transplant. Leukemias were retransplantable, and the immunophenotypes, gene rearrangements and expression profiles were identical or similar to those of the original primary samples. NOD-scid mice transplanted with the same primary samples developed similar leukemias with only a slightly longer latency than did NOD-scid-IL2Rg(-/-) mice. In this highly sensitive NOD-scid-IL2Rg(-/-)-based assay, 1-100 unsorted primary human ALL cells from five of five tested patients, four of whom eventually experienced leukemia relapse, generated leukemias in recipient mice. This very high frequency of LSCs suggests that a hierarchical LSC model is not valuable for poor-outcome ALL.

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References

Castor A, Nilsson L, Astrand-Grundstrom I, Buitenhuis M, Ramirez C, Anderson K . Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med. 2005; 11(6):630-7. DOI: 10.1038/nm1253. View

Lock R, Liem N, Farnsworth M, Milross C, Xue C, Tajbakhsh M . The nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of childhood acute lymphoblastic leukemia reveals intrinsic differences in biologic characteristics at diagnosis and relapse. Blood. 2002; 99(11):4100-8. DOI: 10.1182/blood.v99.11.4100. View

Matsui W, Huff C, Wang Q, Malehorn M, Barber J, Tanhehco Y . Characterization of clonogenic multiple myeloma cells. Blood. 2003; 103(6):2332-6. PMC: 3311914. DOI: 10.1182/blood-2003-09-3064. View

Barabe F, Kennedy J, Hope K, Dick J . Modeling the initiation and progression of human acute leukemia in mice. Science. 2007; 316(5824):600-4. DOI: 10.1126/science.1139851. View

Levis M, Murphy K, Pham R, Kim K, Stine A, Li L . Internal tandem duplications of the FLT3 gene are present in leukemia stem cells. Blood. 2005; 106(2):673-80. PMC: 1895185. DOI: 10.1182/blood-2004-05-1902. View

Pui C, Evans W . Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006; 354(2):166-78. DOI: 10.1056/NEJMra052603. View

Liem N, Papa R, Milross C, Schmid M, Tajbakhsh M, Choi S . Characterization of childhood acute lymphoblastic leukemia xenograft models for the preclinical evaluation of new therapies. Blood. 2004; 103(10):3905-14. DOI: 10.1182/blood-2003-08-2911. 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

Agliano A, Martin-Padura I, Mancuso P, Marighetti P, Rabascio C, Pruneri G . Human acute leukemia cells injected in NOD/LtSz-scid/IL-2Rgamma null mice generate a faster and more efficient disease compared to other NOD/scid-related strains. Int J Cancer. 2008; 123(9):2222-7. DOI: 10.1002/ijc.23772. View

10.

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

11.

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

12.

Monaco G, Konopleva M, Munsell M, Leysath C, Wang R, Ellen Jackson C . Engraftment of acute myeloid leukemia in NOD/SCID mice is independent of CXCR4 and predicts poor patient survival. Stem Cells. 2004; 22(2):188-201. DOI: 10.1634/stemcells.22-2-188. View

13.

Lumkul R, Gorin N, Malehorn M, Hoehn G, Zheng R, Baldwin B . Human AML cells in NOD/SCID mice: engraftment potential and gene expression. Leukemia. 2002; 16(9):1818-26. DOI: 10.1038/sj.leu.2402632. View

14.

le Viseur C, Hotfilder M, Bomken S, Wilson K, Rottgers S, Schrauder A . In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell. 2008; 14(1):47-58. PMC: 2572185. DOI: 10.1016/j.ccr.2008.05.015. View

15.

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

16.

Kong Y, Yoshida S, Saito Y, Doi T, Nagatoshi Y, Fukata M . CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL. Leukemia. 2008; 22(6):1207-13. DOI: 10.1038/leu.2008.83. View

17.

Shultz L, Ishikawa F, Greiner D . Humanized mice in translational biomedical research. Nat Rev Immunol. 2007; 7(2):118-30. DOI: 10.1038/nri2017. View

18.

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

19.

Kennedy J, Barabe F, Poeppl A, Wang J, Dick J . Comment on "Tumor growth need not be driven by rare cancer stem cells". Science. 2007; 318(5857):1722. DOI: 10.1126/science.1149590. View

20.

Cheung A, Fung T, Fan A, Wan T, Chow H, Leung J . Successful engraftment by leukemia initiating cells in adult acute lymphoblastic leukemia after direct intrahepatic injection into unconditioned newborn NOD/SCID mice. Exp Hematol. 2009; 38(1):3-10. DOI: 10.1016/j.exphem.2009.10.007. View