The Mll-Een knockin fusion gene enhances proliferation of myeloid progenitors derived from mouse embryonic stem cells and causes myeloid leukaemia in chimeric mice.
Rearrangement of the mixed lineage leukaemia (MLL) gene with extra eleven nineteen (EEN) was previously identified in an infant with acute myeloid leukaemia. Using homologous recombination, we have created a mouse equivalent of the human MLL-EEN allele and showed that when Mll(Een/+) embryonic stem (ES) cells were induced to differentiate in vitro into haemopoietic cells, there was increased proliferation of myeloid progenitors with self-renewal property. We also generated Mll(Een/+) chimeric mice, which developed leukaemia displaying enlarged livers, spleens, thymuses and lymph nodes owing to infiltration of Mll(Een/+)-expressing leukemic cells. Immunophenotyping of cells from enlarged organs and bone marrow (BM) of the Mll(Een/+) chimeras revealed an accumulation of Mac-1+/Gr-1- immature myeloid cells and a reduction in normal B- and T-cell populations. We observed differential regulation of Hox genes between myeloid cells derived from Mll(Een/+) ES cells and mouse BM leukemic cells which suggested different waves of Hox expression may be activated by MLL fusion proteins for initiation (in ES cells) and maintenance (in leukemic cells) of the disease. We believe studies of MLL fusion proteins in ES cells combined with in vivo animal models offer new approaches to the dissection of molecular events in multistep pathogenesis of leukaemia.
Kong
C T
CT
SH Ho Foundation Research Laboratories in the Department of Pathology, Hong Kong Jockey Club Clinical Research Centre, Hong Kong SAR, China.
Sham
M H
MH
So
C W E
CW
Cheah
K S E
KS
Chen
S J
SJ
Chan
L C
LC
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002455:Cell Division / Q000502:physiology; D002678:Chimera; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D005801:Genes, Homeobox / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000502:physiology; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000473:pathology* / Q000502:physiology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D014178:Translocation, Genetic
D047908:Intracellular Signaling Peptides and Proteins; C105159:SH3GL1 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein