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Blood, 15 July 2006, Vol. 108, No. 2, pp. 669-677.
Prepublished online as a Blood First Edition Paper on March 21, 2006; DOI 10.1182/blood-2005-08-3498.
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Submitted August 31, 2005
Accepted March 2, 2006
A murine Mll-AF4 knockin model results in lymphoid and myeloid deregulation and hematological malignancy
Weili Chen, Quanzhi Li, Wendy A Hudson, Ashish Kumar, Nicole Kirchhof, and John H Kersey*
Cancer Center, University of Minnesota, Minneapolis, MN, USA
Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA
Veterinary Diagnostic Lab & Cancer Center Histopathology, University of Minnesota, St. Paul, MN, USA
Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis, MN, USA
* Corresponding author; email: kerse001{at}umn.edu.
The two most frequent human MLL hematopoietic malignancies involve either AF4 or AF9 as fusion partners; each has distinct biology but the role of the fusion partner is not clear. We produced Mll-AF4 knockin (KI) mice by homologous recombination in embryonic stem cells and compared them with Mll-AF9 KI mice. Young Mll-AF4 mice had lymphoid and myeloid deregulation manifest by increased lymphoid and myeloid cells in hematopoietic organs. In vitro, bone marrow cells from young mice formed unique mixed pro-B lymphoid (B220+CD19+CD43+sIgM-, PAX5 +, TdT+, IgH rearranged)/ myeloid (CD11b/Mac1+, c-fms+, lysozyme+) colonies when grown in IL-7 and Flt3 ligand-containing media. Mixed lymphoid/myeloid hyperplasia and hematological malignancies (most frequently B cell lymphomas) developed in Mll-AF4 mice after prolonged latency; long latency to malignancy indicates that Mll-AF4 induced lymphoid/myeloid deregulation alone is insufficient to produce malignancy. In contrast, young Mll-AF9 mice had predominately myeloid deregulation in vivo and in vitro and developed myeloid malignancies. The early onset of distinct mixed lymphoid/myeloid lineage deregulation in Mll-AF4 mice shows evidence for both "instructive" and "non-instructive" roles for AF4 and AF9 as partners in MLL fusion genes. The molecular basis for "instruction" and secondary cooperating mutations can now be studied in our Mll-AF4 model.
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