Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia - PubMed (original) (raw)

. 2008 Jun 15;111(12):5672-82.

doi: 10.1182/blood-2007-09-108175. Epub 2008 Apr 3.

Paolo Gorello, Ting Liu, Sabire Ehret, Roberta La Starza, Cecile Desjobert, Florent Baty, Martin Brutsche, Padma-Sheila Jayaraman, Alessandra Santoro, Christina Mecucci, Juerg Schwaller

Affiliations

• PMID: 18388181
• DOI: 10.1182/blood-2007-09-108175

Free article

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

Dragana Jankovic et al. Blood. 2008.

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Abstract

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.

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