Bone Marrow Mesenchymal Stem Cells from Infants with MLL-AF4+ Acute Leukemia Harbor and Express the MLL-AF4 Fusion Gene

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2009 Dec 10

PMID 19995953

Citations 62

Authors

Pablo Menendez

Purificacion Catalina

Rene Rodriguez

Gustavo J Melen

Clara Bueno

Mar Arriero

Felix Garcia-Sanchez

Alvaro Lassaletta

Ramon Garcia-Sanz

Javier Garcia-Castro

Affiliations

Soon will be listed here.

Abstract

MLL-AF4 fusion is a hallmark genetic abnormality in infant B-acute lymphoblastic leukemia (B-ALL) known to arise in utero. The cellular origin of leukemic fusion genes during human development is difficult to ascertain. The bone marrow (BM) microenvironment plays an important role in the pathogenesis of several hematological malignances. BM mesenchymal stem cells (BM-MSC) from 38 children diagnosed with cytogenetically different acute leukemias were screened for leukemic fusion genes. Fusion genes were absent in BM-MSCs of childhood leukemias carrying TEL-AML1, BCR-ABL, AML1-ETO, MLL-AF9, MLL-AF10, MLL-ENL or hyperdiploidy. However, MLL-AF4 was detected and expressed in BM-MSCs from all cases of MLL-AF4(+) B-ALL. Unlike leukemic blasts, MLL-AF4(+) BM-MSCs did not display monoclonal Ig gene rearrangements. Endogenous or ectopic expression of MLL-AF4 exerted no effect on MSC culture homeostasis. These findings suggest that MSCs may be in part tumor-related, highlighting an unrecognized role of the BM milieu on the pathogenesis of MLL-AF4(+) B-ALL. MLL-AF4 itself is not sufficient for MSC transformation and the expression of MLL-AF4 in MSCs is compatible with a mesenchymal phenotype, suggesting a differential impact in the hematopoietic system and mesenchyme. The absence of monoclonal rearrangements in MLL-AF4(+) BM-MSCs precludes the possibility of cellular plasticity or de-differentiation of B-ALL blasts and suggests that MLL-AF4 might arise in a population of prehematopoietic precursors.

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References

Waller E, Olweus J, Lund-Johansen F, Huang S, Nguyen M, Guo G . The "common stem cell" hypothesis reevaluated: human fetal bone marrow contains separate populations of hematopoietic and stromal progenitors. Blood. 1995; 85(9):2422-35. View

Walkley C, Olsen G, Dworkin S, Fabb S, Swann J, McArthur G . A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell. 2007; 129(6):1097-110. PMC: 1974882. DOI: 10.1016/j.cell.2007.05.014. View

Thomas M, Gessner A, Vornlocher H, Hadwiger P, Greil J, Heidenreich O . Targeting MLL-AF4 with short interfering RNAs inhibits clonogenicity and engraftment of t(4;11)-positive human leukemic cells. Blood. 2005; 106(10):3559-66. DOI: 10.1182/blood-2005-03-1283. View

Gabert J, Beillard E, van der Velden V, Bi W, Grimwade D, Pallisgaard N . 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. DOI: 10.1038/sj.leu.2403135. View

Cossu G, Bianco P . Mesoangioblasts--vascular progenitors for extravascular mesodermal tissues. Curr Opin Genet Dev. 2003; 13(5):537-42. DOI: 10.1016/j.gde.2003.08.001. View

Lopez-Perez R, Garcia-Sanz R, Gonzalez D, Balanzategui A, Chillon M, Alaejos I . The detection of contaminating clonal cells in apheresis products is related to response and outcome in multiple myeloma undergoing autologous peripheral blood stem cell transplantation. Leukemia. 2000; 14(8):1493-9. DOI: 10.1038/sj.leu.2401862. View

Jansen M, van der Velden V, van Dongen J . Efficient and easy detection of MLL-AF4, MLL-AF9 and MLL-ENL fusion gene transcripts by multiplex real-time quantitative RT-PCR in TaqMan and LightCycler. Leukemia. 2005; 19(11):2016-8. DOI: 10.1038/sj.leu.2403939. View

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D . Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006; 8(4):315-7. DOI: 10.1080/14653240600855905. View

Menendez P, Wang L, Chadwick K, Li L, Bhatia M . Retroviral transduction of hematopoietic cells differentiated from human embryonic stem cell-derived CD45(neg)PFV hemogenic precursors. Mol Ther. 2004; 10(6):1109-20. DOI: 10.1016/j.ymthe.2004.08.016. View

10.

Reya T, Morrison S, Clarke M, Weissman I . Stem cells, cancer, and cancer stem cells. Nature. 2001; 414(6859):105-11. DOI: 10.1038/35102167. View

11.

Wiemels J, Kang M, Greaves M . Backtracking of leukemic clones to birth. Methods Mol Biol. 2009; 538:7-27. DOI: 10.1007/978-1-59745-418-6_2. View

12.

Jiang J, Hui C . Hedgehog signaling in development and cancer. Dev Cell. 2008; 15(6):801-12. PMC: 6443374. DOI: 10.1016/j.devcel.2008.11.010. View

13.

Greaves M, Wiemels J . Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer. 2003; 3(9):639-49. DOI: 10.1038/nrc1164. View

14.

Corre J, Mahtouk K, Attal M, Gadelorge M, Huynh A, Fleury-Cappellesso S . Bone marrow mesenchymal stem cells are abnormal in multiple myeloma. Leukemia. 2007; 21(5):1079-88. PMC: 2346535. DOI: 10.1038/sj.leu.2404621. View

15.

Ford A, Ridge S, Cabrera M, Mahmoud H, Steel C, Chan L . In utero rearrangements in the trithorax-related oncogene in infant leukaemias. Nature. 1993; 363(6427):358-60. DOI: 10.1038/363358a0. View

16.

Beillard E, Pallisgaard N, van der Velden V, Bi W, Dee R, van der Schoot E . Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using 'real-time' quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) - a Europe against cancer program. Leukemia. 2003; 17(12):2474-86. DOI: 10.1038/sj.leu.2403136. View

17.

Montes R, Ligero G, Sanchez L, Catalina P, De La Cueva T, Nieto A . Feeder-free maintenance of hESCs in mesenchymal stem cell-conditioned media: distinct requirements for TGF-beta and IGF-II. Cell Res. 2009; 19(6):698-709. DOI: 10.1038/cr.2009.35. View

18.

Gunsilius E, Duba H, Petzer A, Kahler C, Grunewald K, Stockhammer G . Evidence from a leukaemia model for maintenance of vascular endothelium by bone-marrow-derived endothelial cells. Lancet. 2000; 355(9216):1688-91. DOI: 10.1016/S0140-6736(00)02241-8. View

19.

Gonzalez D, Gonzalez M, Balanzategui A, Sarasquete M, Lopez-Perez R, Chillon M . Molecular characteristics and gene segment usage in IGH gene rearrangements in multiple myeloma. Haematologica. 2005; 90(7):906-13. View

20.

Wei W, Sedivy J . Differentiation between senescence (M1) and crisis (M2) in human fibroblast cultures. Exp Cell Res. 1999; 253(2):519-22. DOI: 10.1006/excr.1999.4665. View