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

Abstract

We have studied a patient with acute myeloid leukemia (AML) and t(10;11)(q23; p15) as the sole cytogenetic abnormality.

PRH/HHex inhibits the migration of breast and prostate epithelial cells through direct transcriptional regulation of Endoglin

“…Furthermore in one human AML the only characterised genetic change is a fusion of the prh gene with the nucleoporin gene Nup98 and this is thought to decrease the activity of endogenous PRH (11). We have shown that in a CML cell line, BCR-ABL activity indirectly results in the down-regulation of PRH transcriptional repression activity and the derepression of several PRH target genes including Vegfa, Vegfr-1, and Vegfr-2 (13).…”

“…Moreover, in human T-cell leukaemias associated with the aberrant expression of the LMO2 oncogene, elevated PRH expression is necessary for development of the disease (7,8). However, more generally, it is the disruption of PRH activity that is associated with a variety of diseases states (9)(10)(11)(12).…”

Leukemogenic properties of NUP98-PMX1 are linked to NUP98 and homeodomain sequence functions but not to binding properties of PMX1 to serum response factor

“…To gain insight into the molecular mechanisms underlying the leukemogenicity of NUP98-PMX1, we quantitatively assessed Hoxa cluster gene expression in mouse stem cell virus-yellow fluorescent protein (MIY) empty vector control, PMX1, NUP98-PMX1 and NUP98-PMX1-N51Q-transduced lineage depleted, Sca1 þ (Lin-Sca þ ) BM cells. Similar to NUP98-HOXD13 (Palmqvist et al, 2007), NUP98-NSD1 (Wang et al, 2007) and NUP98-HHEX (Jankovic et al, 2008), NUP98-PMX1 strongly activated multiple Hoxa cluster genes, including Hoxa5 to Hoxa10, compared with MIY control and the non-leukemogenic PMX1 and NUP98-PMX1(N51Q) (Figure 7a, left panel). Furthermore, only NUP98-PMX1 activated expression of Bmi1, Flt3 and Cd34 (Figure 7a, right panel), genes associated with hematopoietic and LSCs (Wang et al, 2006;Argiropoulos and Humphries, 2007).…”

“…The nucleoporin gene NUP98 on chromosome 11p15 is involved in chromosomal rearrangements with at least 20 different partners (Slape and Aplan, 2004;Nakamura, 2005;Romana et al, 2006;Jankovic et al, 2008). NUP98 translocations have been described in de novo acute and chronic leukemias, as well as therapyrelated myelodysplastic syndrome and therapy-related acute myeloid leukemia (AML).…”

NUP98–HMGB3: a novel oncogenic fusion

“…Mouse models developed to analyze the oncogenic activity of MLL and NUP98 fusions showed the overexpression of Hoxa9 and Meis1 in blast cells; 4,5,[15][16][17][18] in addition, Hoxa9 and Meis1 overexpression was associated with the emergence but not the maintenance of MLL leukemic stem cells. 9 We thus measured the expression levels of genes of the Hoxa cluster as well as the genes encoding for the HOX cofactors Meis1, Pbx1 and Pbx3 in BM cells from primary and secondary NUP98-HMGB3 recipients.…”