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

• Published in: Blood 2008-06, Vol.111 (12), p.5672-5682
• Main Authors: Jankovic, Dragana, Gorello, Paolo, Liu, Ting, Ehret, Sabire, La Starza, Roberta, Desjobert, Cecile, Baty, Florent, Brutsche, Martin, Jayaraman, Padma-Sheila, Santoro, Alessandra, Mecucci, Christina, Schwaller, Juerg
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone Marrow Cells - pathology; Bone Marrow Cells - physiology; Chlorocebus aethiops; COS Cells; Gene Expression Profiling; Gene Expression Regulation, Leukemic; HeLa Cells; Hematologic and hematopoietic diseases; Homeodomain Proteins - genetics; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Leukemia, Myeloid, Acute - therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Mice; Mice, Inbred BALB C; Middle Aged; Neoplasm Transplantation; NIH 3T3 Cells; Nuclear Pore Complex Proteins - genetics; Oncogene Proteins, Fusion - genetics; Transcription Factors - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-09-108175

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.