High FUS/TLS expression in acute myeloid leukaemia samples

Abstract

Retinoic acid has the ability to induce differentiation in some myeloid leukaemia cell lines and has been used to induce remission in acute promyelocytic leukaemia patients. We have analysed changes in gene expression, by differential display, in HL60 cells exposed to all-trans retinoic acid (ATRA) for only 1 h. Only about 0.4% of the genes examined by this technique showed changes in expression level, and all four of the gene fragments identified were downregulated during the short 1 h exposure. Two of the fragments were novel, a third was MYC and the fourth was the FUS proto-oncogene. Northern analysis showed that FUS was downregulated within 1 h only during induced neutrophil differentiation but not at all during induced monocyte differentiation. Unlike the sensitive cell lines, ATRA-resistant cell lines did not show a downregulation of FUS over a 24 h period of exposure to ATRA. Using a semiquantitative PCR analysis, no difference in FUS levels was observed between ATRA-sensitive and -resistant cell lines. A similar analysis was carried out on primary acute myeloid leukaemia (AML), peripheral stem cell harvests (PBSC) and cord blood samples. The PBSC and cord blood samples had FUS levels that were similar or generally less than the cell lines. However, much higher levels were seen in 63% of the AML samples examined. The data presented are consistent with previous reports for a role for FUS in the promotion and maintenance of cellular proliferation.

Post-transcriptional mechanisms in BCR/ABL leukemogenesis: role of shuttling RNA-binding proteins

“…FUS expression and DNA binding activity is induced by BCR/ABL in hematopoietic cells (Perrotti et al, 1998). FUS expression is downregulated in the early stages of ATRA-induced granulocytic differentiation of HL 60 leukemia cells (Mills et al, 2000). This finding may reflect the changes in gene expression associated with terminal differentiation (Lian et al, 2001) or may be causally linked to the commitment to terminal differentiation.…”

ALS-Associated FUS Mutations Result in Compromised FUS Alternative Splicing and Autoregulation

“…Conversely, high levels of FUS are associated with cancer and ALS, and moreover, are known genetic determinants of these diseases. Overexpression of FUS is observed in liposarcoma and leukemia with FUS translocations [54], [55]. Aberrant accumulation of FUS mutant protein is a characteristic pathology of FUS-associated ALS [8], [9].…”

The oncofusion protein FUS–ERG targets key hematopoietic regulators and modulates the all-trans retinoic acid signaling pathway in t(16;21) acute myeloid leukemia

“…FUS expression is downregulated in the early stages of ATRA-induced granulocytic differentiation of HL60 leukemic cells. 15 , 16 Furthermore, a knockout study showed that Fus null mice have an increased number of granulocytes. 17 Another study with Fus -deficient mice showed that Fus −/− fetal livers developed normally, except for a mild reduction in numbers of hematopoietic stem and progenitor cells compared with wild type (WT).…”