Enforced expression of the homeobox gene Mixl1 impairs hematopoietic differentiation and results in acute myeloid leukemia.
Mixl1, the sole murine homologue of the Xenopus Mix/Bix family of homeobox transcription factors, is essential for the patterning of axial mesendodermal structures during early embryogenesis. Gene targeting and overexpression studies have implicated Mixl1 as a regulator of hematopoiesis arising in differentiating embryonic stem cells. To assess the role of Mixl1 in the regulation of adult hematopoiesis, we overexpressed Mixl1 in murine bone marrow using a retroviral transduction/transplantation model. Enforced expression of Mixl1 profoundly perturbed hematopoietic lineage commitment and differentiation, giving rise to abnormal myeloid progenitors and impairing erythroid and lymphoid differentiation. Moreover, all mice reconstituted with Mixl1-transduced bone marrow developed fatal, transplantable acute myeloid leukemia with a mean latency period of 200 days. These observations establish a link between enforced Mixl1 expression and leukemogenesis in the mouse.
Glaser
Stefan
S
The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3050, Australia.
Metcalf
Donald
D
Wu
Li
L
Hart
Adam H
AH
DiRago
Ladina
L
Mifsud
Sandra
S
D'Amico
Angela
A
Dagger
Samantha
S
Campo
Chiara
C
Chan
Angela C
AC
Izon
David J
DJ
Robb
Lorraine
L
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006410:Hematopoiesis; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D015996:Survival Rate
D018398:Homeodomain Proteins; C464781:Mixl1 protein, mouse