Publication

Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia

Journal Paper/Review - Jun 15, 2008

Units
PubMed
Doi

Citation
Jankovic D, Mecucci C, Santoro A, Jayaraman P, Brutsche M, Baty F, Desjobert C, La Starza R, Ehret S, Liu T, Gorello P, Schwaller J. Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia. Blood 2008; 111:5672-82.
Type
Journal Paper/Review (English)
Journal
Blood 2008; 111
Publication Date
Jun 15, 2008
Issn Electronic
1528-0020
Pages
5672-82
Brief description/objective

We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23;p15) as the sole cytogenetic abnormality. Molecular analysis revealed a translocation involving nucleoporin 98 (NUP98) fused to the DNA-binding domain of the hematopoietically expressed homeobox gene (HHEX). Expression of NUP98/HHEX in murine bone marrow cells leads to aberrant self-renewal and a block in normal differentiation that depends on the integrity of the NUP98 GFLG repeats and the HHEX homeodomain. Transplantation of bone marrow cells expressing NUP98/HHEX leads to transplantable acute leukemia characterized by extensive infiltration of leukemic blasts expressing myeloid markers (Gr1(+)) as well as markers of the B-cell lineage (B220(+)). A latency period of 9 months and its clonal character suggest that NUP98/HHEX is necessary but not sufficient for disease induction. Expression of EGFP-NUP98/HHEX fusions showed a highly similar nuclear localization pattern as for other NUP98/homeodomain fusions, such as NUP98/HOXA9. Comparative gene expression profiling in primary bone marrow cells provided evidence for the presence of common targets in cells expressing NUP98/HOXA9 or NUP98/HHEX. Some of these genes (Hoxa5, Hoxa9, Flt3) are deregulated in NUP98/HHEX-induced murine leukemia as well as in human blasts carrying this fusion and might represent bona fide therapeutic targets.