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Klin Padiatr 2007; 219(6): 306-311
DOI: 10.1055/s-2007-985878
Review Article

© 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 StrategienJ. Faber 1 , S. A. Armstrong 1
  • 1Division of Hematology/Oncology, Children's Hospital, Department of Pediatric Oncology, Dana Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts, USA
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Publication History

Publication Date:
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

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Korrespondenzadresse

S.A. ArmstrongMD,PhD 

Children's Hospital BostonKarp Family Research Laboratories

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Phone: +1/617/919 25 08

Fax: +1/617/730 09 34

Email: Scott.Armstrong@childrens.harvard.edu

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