Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia.
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.
Jankovic
Dragana
D
Department of Research, University Hospital Basel, Basel, Switzerland.
Gorello
Paolo
P
Liu
Ting
T
Ehret
Sabire
S
La Starza
Roberta
R
Desjobert
Cecile
C
Baty
Florent
F
Brutsche
Martin
M
Jayaraman
Padma-Sheila
PS
Santoro
Alessandra
A
Mecucci
Christina
C
Schwaller
Juerg
J
D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology / Q000502:physiology; D019556:COS Cells; D002522:Chlorocebus aethiops; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D041681:NIH 3T3 Cells; D009368:Neoplasm Transplantation; D028861:Nuclear Pore Complex Proteins / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
C078492:HHEX protein, human; D018398:Homeodomain Proteins; D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors