1. ¹SH Ho Foundation Research Laboratories in the Department of Pathology, Hong Kong Jockey Club Clinical Research Centre, Hong Kong SAR, China
2. ²Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
3. ³Section of Haemato-Oncology, Institute of Cancer Research, Sutton, UK
4. ⁴State Key Lab of Medical Genomics, Shanghai Institute of Hematology, Ruijin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Correspondence: Professor LC Chan, Department of Pathology, Division of Haemotology, The University of Hong Kong, University Pathology Building, Queen Mary Hospital, 102 Pokfulam Road, Pokfulam, Hong Kong SAR, China. E-mail: chanlc@pathology.hku.hk

⁵These authors contribute equally to this work.

Received 24 March 2006; Revised 14 June 2006; Accepted 21 June 2006; Published online 3 August 2006.

Abstract

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.