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DOI: 10.1055/s-2007-985878
© Georg Thieme Verlag KG Stuttgart · New York
Defining Leukemia Stem Cells in MLL-Translocated Leukemias: Implications for Novel Therapeutic Strategies
Charakterisierung von Leukämie-Stammzellen in MLL-translozierten Leukämien: Implikationen für neue therapeutische StrategienPublikationsverlauf
Publikationsdatum:
30. November 2007 (online)
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Abstract
Hematological malignancies and probably many other tumors are dependent on highly proliferating and self-renewing cancer stem cells. An important question in the development of novel, less toxic antileukemic strategies specifically targeting leukemia stem cells is how closely leukemia stem cells are related to normal hematopoietic stem cells. It has been recently demonstrated that leukemia stem cells can be derived from different stages in normal hematopoiesis and have unique phenotypic and genetic features. Introduction of Mixed-lineage leukemia (MLL)-fusion oncoproteins, frequently found in infant leukemias and therapy-related leukemias, into differentiated hematopoietic progenitor cells results in the generation of leukemias with a high frequency of leukemia stem cells. The progenitor-derived leukemia stem cells ectopically express a limited stem cell program while maintaining the global identity of differentiated myeloid cells. Development of therapeutic strategies that specifically target the leukemia stem cell program while sparing normal hematopoietic stem cells may represent a novel therapeutic approach in human leukemias with high efficacy yet less side effects.
Zusammenfassung
Die Entstehung von Leukämien und sehr wahrscheinlich vielen anderen Malignomen ist von stark proliferierenden und sich selbst erneuernden Krebs-Stammzellen abhängig. Eine wichtige Voraussetzung für die Entwicklung neuer Therapieoptionen, welche spezifisch auf Krebs-Stammzellen abzielen, sind detaillierte Kenntnisse darüber, wie eng Krebs-Stammzellen mit normalen Körperstammzellen verwandt sind. Für Leukämie-Stammzellen konnte kürzlich gezeigt werden, dass sie sich von verschiedenen Entwicklungsstufen der Hämatopoese ableiten können und dass sie einzigartige phänotypische und molekulargenetische Eigenschaften besitzen, die sie von normalen Körperstammzellen unterscheiden. So führt das Einbringen von MLL-Fusions-Onkoproteinen, welche häufig bei Leukämien im Säuglingsalter und bei Therapie-assoziierten Leukämien vorgefunden werden, in differenzierte Granulozyten-Makrophagen Progenitorzellen zu Leukämien mit einem hohen Anteil von Leukämie-Stammzellen. Diese Leukämie-Stammzellen aktivieren ein umschriebenes Stammzell-Programm, bewahren jedoch die globale Identität ihrer normalen Ursprungszellen, aus denen sie entstehen. Die Entwicklung neuer therapeutischer Strategien, welche gezielt Leukämie-Stammzell-spezifische Programme mo-dulieren und dabei normale hämatopoetische Stammzellen aussparen, ist ein viel versprechender neuer Ansatz zur Verbesserung der therapeutischen Effizienz bei einer geringeren Nebenwirkungsrate.
Key words
mixed-lineage leukemia - leukemia stem cells - targeted therapy
Schlüsselwörter
Mixed-lineage Leukemia - Stammzellen - gezielte Therapie
References
- 1 Aigner A. Gene silencing through RNA interference (RNAi) in vivo: strategies based on the direct application of siRNAs. J Biotechnol. 2006; 124 12-25
- 2 Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003; 100 3983-3988
- 3 Armstrong SA, Staunton JE, Silverman LB, Pieters R, Boer ML den, Minden MD, Sallan SE, Lander ES, Golub TR, Korsmeyer SJ. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet. 2002; 30 41-47
- 4 Ayton PM, Cleary ML. Transformation of myeloid progenitors by MLL oncoproteins is dependent on Hoxa7 and Hoxa9. Genes Dev. 2003; 17 2298-2307
- 5 Barabe F, Kennedy JA, Hope KJ, Dick JE. Modeling the initiation and progression of human acute leukemia in mice. Science. 2007; 316 600-604
- 6 Biondi A, Cimino G, Pieters R, Pui CH. Biological and therapeutic aspects of infant leukemia. Blood. 2000; 96 24-33
- 7 Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997; 3 730-737
- 8 Borkhardt A, Heidenreich O. RNA interference as a potential tool in the treatment of leukaemia. Expert Opin Biol Ther. 2004; 4 1921-1929
- 9 Borkhardt A, Wuchter C, Viehmann S, Pils S, Teigler-Schlegel A, Stanulla M, Zimmermann M, Ludwig WD, Janka-Schaub G, Schrappe M, Harbott J. Infant acute lymphoblastic leukemia - combined cytogenetic, immunophenotypical and molecular analysis of 77 cases. Leukemia. 2002; 16 1685-1690
- 10 Chen CS, Sorensen PH, Domer PH, Reaman GH, Korsmeyer SJ, Heerema NA, Hammond GD, Kersey JH. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood. 1993; 81 2386-2393
- 11 Corral J, Lavenir I, Impey H, Warren AJ, Forster A, Larson TA, Bell S, McKenzie AN, King G, Rabbitts TH. An Mll-AF9 fusion gene made by homologous recombination causes acute leukemia in chimeric mice: a method to create fusion oncogenes. Cell. 1996; 85 853-861
- 12 Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL. Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev. 2003; 17 3029-3035
- 13 Deshpande AJ, Cusan M, Rawat VP, Reuter H, Krause A, Pott C, Quintanilla-Martinez L, Kakadia P, Kuchenbauer F, Ahmed F, Delabesse E, Hahn M, Lichter P, Kneba M, Hiddemann W, Macintyre E, Mecucci C, Ludwig WD, Humphries RK, Bohlander SK, Feuring-Buske M, Buske C. Acute myeloid leukemia is propagated by a leukemic stem cell with lymphoid characteristics in a mouse model of CALM/AF10-positive leukemia. Cancer Cell. 2006; 10 363-374
- 14 Du Y, Spence SE, Jenkins NA, Copeland NG. Cooperating cancer-gene identification through oncogenic-retrovirus-induced insertional mutagenesis. Blood. 2005; 106 2498-2505
- 15 Faber J, Krivtsov AV, Stubbs MC, Wright R, Heuvel-Eibrink M van den, Kung A, Zwaan CM, Armstrong SA. HoxA9 knockdown inhibits proliferation and induces cell death in human MLL-rearranged Leukemias. Blood. 2006; 108 220
- 16 Felix CA, Hosler MR, Winick NJ, Masterson M, Wilson AE, Lange BJ. ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children. Blood. 1995; 85 3250-3256
- 17 Ferrando AA, Armstrong SA, Neuberg DS, Sallan SE, Silverman LB, Korsmeyer SJ, Look AT. Gene expression signatures in MLL-rearranged T-lineage and B-precursor acute leukemias: dominance of HOX dysregulation. Blood. 2003; 102 262-268
- 18 Fuchs U, Borkhardt A. The application of siRNA technology to cancer biology discovery. Adv Cancer Res. 2007; 96 75-102
- 19 Gessner A, Thomas M, Greil J, Heidenreich O. SiRNA-mediated MLL-AF4 knockdown affects hTERT expression. Klin Padiatr. 2006; 218 187
- 20 Griffin JD, Lowenberg B. Clonogenic cells in acute myeloblastic leukemia. Blood. 1986; 68 1185-1195
- 21 Gudowius S, Recker K, Laws HJ, Dirksen U, Troger A, Wieczorek U, Furlan S, Gobel U, Hanenberg H. Identification of candidate target antigens for antibody-based immunotherapy in childhood B-cell precursor ALL. Klinische Padiatrie. 2006; 218 327-333
- 22 Guzman ML, Rossi RM, Karnischky L, Li X, Peterson DR, Howard DS, Jordan CT. The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood. 2005; 105 4163-4169
- 23 Heerema NA, Arthur DC, Sather H, Albo V, Feusner J, Lange BJ, Steinherz PG, Zeltzer P, Hammond D, Reaman GH. Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukemia: impact of the 11q23 breakpoint on outcome: a report of the Childrens Cancer Group. Blood. 1994; 83 2274-2284
- 24 Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N, Rowan R, Amaral S, Curley D, Williams IR, Akashi K, Gilliland DG. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell. 2004; 6 587-596
- 25 Huret JL, Dessen P, Bernheim A. An atlas of chromosomes in hematological malignancies. Example: 11q23 and MLL partners. Leukemia. 2001; 15 987-989
- 26 Jamieson CH, Ailles LE, Dylla SJ, Muijtjens M, Jones C, Zehnder JL, Gotlib J, Li K, Manz MG, Keating A, Sawyers CL, Weissman IL. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N Engl J Med. 2004; 351 657-667
- 27 Jansen MW, Corral L, Velden VH van der, Panzer-Grumayer R, Schrappe M, Schrauder A, Marschalek R, Maeyer C, Boer ML den, Hop WJ, Valsecchi MG, Basso G, Biondi A, Pieters R, Dongen JJ van. Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement. Leukemia. 2007; 21 633-641
- 28 Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006; 12 1167-1174
- 29 Kim CF, Jackson EL, Woolfenden AE, Lawrence S, Babar I, Vogel S, Crowley D, Bronson RT, Jacks T. Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell. 2005; 121 823-835
- 30 Krause DS, Lazarides K, Andrian UH van, Etten RA Van. Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat Med. 2006; 12 1175-1180
- 31 Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J, Levine JE, Wang J, Hahn WC, Gilliland DG, Golub TR, Armstrong SA. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006; 442 818-822
- 32 Kroon E, Krosl J, Thorsteinsdottir U, Baban S, Buchberg AM, Sauvageau G. Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. Embo J. 1998; 17 3714-3725
- 33 Lamb J, Crawford ED, Peck D, Modell JW, Blat IC, Wrobel MJ, Lerner J, Brunet JP, Subramanian A, Ross KN, Reich M, Hieronymus H, Wei G, Armstrong SA, Haggarty SJ, Clemons PA, Wei R, Carr SA, Lander ES, Golub TR. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006; 313 1929-1935
- 34 Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994; 367 645-648
- 35 Lavau C, Szilvassy SJ, Slany R, Cleary ML. Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL. Embo J. 1997; 16 4226-4237
- 36 Lawrence HJ, Helgason CD, Sauvageau G, Fong S, Izon DJ, Humphries RK, Largman C. Mice bearing a targeted interruption of the homeobox gene HOXA9 have defects in myeloid, erythroid, and lymphoid hematopoiesis. Blood. 1997; 89 1922-1930
- 37 Meyer C, Schneider B, Jakob S, Strehl S, Attarbaschi A, Schnittger S, Schoch C, Jansen MW, Dongen JJ van, Boer ML den, Pieters R, Ennas MG, Angelucci E, Koehl U, Greil J, Griesinger F, Zur Stadt U, Eckert C, Szczepanski T, Niggli FK, Schafer BW, Kempski H, Brady HJ, Zuna J, Trka J, Nigro LL, Biondi A, Delabesse E, Macintyre E, Stanulla M, Schrappe M, Haas OA, Burmeister T, Dingermann T, Klingebiel T, Marschalek R. The MLL recombinome of acute leukemias. Leukemia. 2006; 20 777-784
- 38 Moorman AV, Raimondi SC, Pui CH, Baruchel A, Biondi A, Carroll AJ, Forestier E, Gaynon PS, Harbott J, Harms DO, Heerema N, Pieters R, Schrappe M, Silverman LB, Vilmer E, Harrison CJ. No prognostic effect of additional chromosomal abnormalities in children with acute lymphoblastic leukemia and 11q23 abnormalities. Leukemia. 2005; 19 557-563
- 39 Moricke A, Zimmermann M, Reiter A, Gadner H, Odenwald E, Harbott J, Ludwig WD, Riehm H, Schrappe M. Prognostic impact of age in children and adolescents with acute lymphoblastic leukemia: data from the trials ALL-BFM 86, 90, and 95. Klin Padiatr. 2005; 217 310-320
- 40 Mrozek K, Heinonen K, Lawrence D, Carroll AJ, Koduru PR, Rao KW, Strout MP, Hutchison RE, Moore JO, Mayer RJ, Schiffer CA, Bloomfield CD. Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: a cancer and leukemia group B study. Blood. 1997; 90 4532-4538
- 41 Pagano L, Fianchi L, Caira M, Rutella S, Leone G. The role of Gemtuzumab Ozogamicin in the treatment of acute myeloid leukemia patients. Oncogene. 2007; 26 3679-3690
- 42 Passegue E, Jamieson CH, Ailles LE, Weissman IL. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics?. Proc Natl Acad Sci USA. 2003; 100 ((Suppl 1)) 11842-11849
- 43 Pui CH, Chessells JM, Camitta B, Baruchel A, Biondi A, Boyett JM, Carroll A, Eden OB, Evans WE, Gadner H, Harbott J, Harms DO, Harrison CJ, Harrison PL, Heerema N, Janka-Schaub G, Kamps W, Masera G, Pullen J, Raimondi SC, Richards S, Riehm H, Sallan S, Sather H, Shuster J, Silverman LB, Valsecchi MG, Vilmer E, Zhou Y, Gaynon PS, Schrappe M. Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia. 2003; 17 700-706
- 44 Reinhardt D, Diekamp S, Fleischhack G, Corbacioglu C, Jurgens H, Dworzak M, Kaspers G, Creutzig U, Zwaan CM. Gemtuzumab ozogamicin (Mylotarg) in children with refractory or relapsed acute myeloid leukemia. Onkologie. 2004; 27 269-272
- 45 Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001; 414 105-111
- 46 Rossig C, Pscherer S, Landmeier S, Altvater B, Jurgens H, Vormoor J. Adoptive cellular immunotherapy with CD19-specific T cells. Klin Padiatr. 2005; 217 351-356
- 47 Rozovskaia T, Feinstein E, Mor O, Foa R, Blechman J, Nakamura T, Croce CM, Cimino G, Canaani E. Upregulation of Meis1 and HoxA9 in acute lymphocytic leukemias with the t(4:11) abnormality. Oncogene. 2001; 20 874-878
- 48 Rubnitz JE, Link MP, Shuster JJ, Carroll AJ, Hakami N, Frankel LS, Pullen DJ, Cleary ML. Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood. 1994; 84 570-573
- 49 Rubnitz JE, Raimondi SC, Tong X, Srivastava DK, Razzouk BI, Shurtleff SA, Downing JR, Pui CH, Ribeiro RC, Behm FG. Favorable impact of the t(9;11) in childhood acute myeloid leukemia. J Clin Oncol. 2002; 20 2302-2309
- 50 Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. German-Austrian-Swiss ALL-BFM Study Group. Blood. 2000; 95 3310-3322
- 51 Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003; 63 5821-5828
- 52 Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature. 2004; 432 396-401
- 53 Somervaille TC, Cleary ML. Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell. 2006; 10 257-268
- 54 Song E, Zhu P, Lee SK, Chowdhury D, Kussman S, Dykxhoorn DM, Feng Y, Palliser D, Weiner DB, Shankar P, Marasco WA, Lieberman J. Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors. Nat Biotechnol. 2005; 23 709-717
- 55 Stegmaier K, Corsello SM, Ross KN, Wong JS, Deangelo DJ, Golub TR. Gefitinib induces myeloid differentiation of acute myeloid leukemia. Blood. 2005; 106 2841-2848
- 56 Stegmaier K, Ross KN, Colavito SA, O'Malley S, Stockwell BR, Golub TR. Gene expression-based high-throughput screening(GE-HTS) and application to leukemia differentiation. Nat Genet. 2004; 36 257-263
- 57 Thomas M, Gessner A, Vornlocher HP, 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 3559-3566
- 58 Wang J, Iwasaki H, Krivtsov A, Febbo PG, Thorner AR, Ernst P, Anastasiadou E, Kutok JL, Kogan SC, Zinkel SS, Fisher JK, Hess JL, Golub TR, Armstrong SA, Akashi K, Korsmeyer SJ. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. Embo J. 2005; 24 368-381
- 59 Warner JK, Wang JC, Hope KJ, Jin L, Dick JE. Concepts of human leukemic development. Oncogene. 2004; 23 7164-7177
- 60 Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Cheng C, Campana D, Wilkins D, Zhou X, Li J, Liu H, Pui CH, Evans WE, Naeve C, Wong L, Downing JR. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002; 1 133-143
- 61 Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, Morrison SJ. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006; 441 475-482
- 62 Zeisig BB, Milne T, Garcia-Cuellar MP, Schreiner S, Martin ME, Fuchs U, Borkhardt A, Chanda SK, Walker J, Soden R, Hess JL, Slany RK. Hoxa9 and Meis1 are key targets for MLL-ENL-mediated cellular immortalization. Mol Cell Biol. 2004; 24 617-628
Korrespondenzadresse
S.A. ArmstrongMD,PhD
Children's Hospital BostonKarp Family Research Laboratories
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eMail: Scott.Armstrong@childrens.harvard.edu