AML1/ETO promotes the maintenance of early hematopoietic progenitors in NOD/SCID mice but does not abrogate their lineage specific differentiation.
AML1-ETO is generated by the t(8;21) translocation found in approximately 12% of acute myelogenous leukemia. Studies to delineate the mechanism by which AML1-ETO induces leukemia have primarily relied on transformed human cell lines or murine model systems. The goal of this study was to determine the effect of AML1-ETO expression on primary human hematopoietic cells in vitro and in a xenograft model. We used a FMEV retroviral vector for the transfer of AML1/ETO into human CD34 + cells. The repopulation, self-renewal, and differentiation potential of infected cells were assessed in serum-free liquid culture, colony assays, and in transplanted NOD-SCID mice. High transcription levels were confirmed by real-time PCR. AML1-ETO expressing cells were expandable for up to 12 weeks and retained an immature morphology. The capacity for prolonged survival, however, did not abrogate maturation, as AML1-ETO cells gave rise to normal colonies in a CFU-assay. AML1/ETO-expressing cells also contributed to myeloid (CD15, CD33), B-lymphoid (CD20), NK-cell (CD56) and erythroid (GPA) lineages in xenografted NOD/SCID mice. Although able to engraft all major lineages, AML1/ETO transplanted cells were primarily found in less differentiated fractions as measured by cell surface markers CD34 and CD38. In spite of a good engraftment and prolonged observation period none of the NOD/SCID-mice developed an acute myelogenous leukemia. Our findings demonstrate that AML1/ETO promotes the maintenance of early human hematopoietic progenitors, but does not abrogate their physiologic differentiation. Furthermore, the leukemogenic potential of AML1/ETO expressed in human progenitors is low, despite transcription levels equivalent to those found in AMLs.
Bäsecke
Jörg
J
Department of Hematology and Oncology, Universitätsklinikum Göttingen, Germany. jbaesec@gwdg.de
Schwieger
Maike
M
Griesinger
Frank
F
Schiedlmeier
Bernd
B
Wulf
Gerald
G
Trümper
Lorenz
L
Stocking
Carol
C
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D007938:Leukemia / Q000209:etiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D014183:Transplantation, Heterologous
C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors