Down-regulation of MLL-AF9, MLL and MYC expression is not obligatory for monocyte-macrophage maturation in AML-M5 cell lines carrying t(9;11)(p22;q23)

Abstract

Abstract. The MLL-AF9 oncogene originates from the translocation t(9;11)(p22;q23), which is mainly associated with monocytic acute myeloid leukaemia (AML-M5; FABclassification). In AML-M5 THP-1 cells carrying t(9;11) (p22;q23) and expressing MLL-AF9, we previously showed that MLL-AF9 expression is down-regulated during monocytemacrophage maturation. We have subsequently observed that in a 'rapid-growing' variant of the THP-1 cell line (THP-1-R) MLL-AF9 down-regulation does not occur. MLL fusion proteins (including MLL-AF9) deregulate MYC transactivation activity, and both presence and absence of MYC downregulation have been reported during monocyte-macrophage maturation in THP-1 cells. In the present study, we analyze the expression patterns of MLL-AF9, MLL wild-type and MYC after induction of monocyte-macrophage terminal differentiation in the AML-M5 cell lines, THP-1, THP-1-R, Mono-Mac-6 (MM6) and MOLM-13, all of which carry t(9;11)(p22;q23) and express MLL-AF9. RT-PCR analysis indicated that down-regulation of MLL-AF9, MLL or MYC is not necessary to abolish malignant phenotypes by induction of terminal monocyte-macrophage differentiation in leukaemic cells carrying t(9;11)(p22;q23).

Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation

“…Knockdown of MLL-MLLT3 has been previously shown to induce differentiation and cessation of cellular proliferation. 37,38 Our analysis suggests that repression of mir-424-503 by MLL-MLLT3 may help maintain proliferation and prevent cell-cycle arrest and differentiation by mir-424 and mir-503, two putative tumor suppressor microRNAs of the mir-15/16 family. 29,39 Discussion Twenty-three microRNAs were identified that are dynamically expressed during monocytic differentiation of the THP-1 AML cell line.…”

Down-regulation of HOXA4, HOXA7, HOXA10, HOXA11 and MEIS1 during monocyte-macrophage differentiation in THP-1 cells

“…Previously, we and others showed that targeted down-regulation of MLL-AF9 in a human leukemia cell line, THP-1, induced strong inhibition of cell proliferation (8,9), but did not affect the terminal differentiation of THP-1 cells (8). Successively, we reported that down-regulation of MLL-AF9 expression is not mandatory for monocyte-macrophage maturation in AML-M5 cells carrying the translocation t(9;11)(p22;q23), hypothesizing that other genes are important for differentiation blockage in leukemogenesis induced by MLL-AF9 (10). In this study, we analyzed the expression patterns of HOXA4, 5,6,7,9,10,11 and MEIS1 by semiquantitative RT-PCR during the monocyte-macrophage differentiation induced by phorbol 12-myristate 13-acetate (PMA) in THP-1 cells.…”

“…Successively, we reported that down-regulation of MLL-AF9 expression is not mandatory for monocyte-macrophage maturation in AML-M5 cells carrying the translocation t(9;11)(p22;q23), hypothesizing that other genes are important for differentiation blockage in leukemogenesis induced by MLL-AF9 (10). In this study, we analyzed the expression patterns of HOXA4, 5,6,7,9,10,11 and MEIS1 by semiquantitative RT-PCR during the monocyte-macrophage differentiation induced by phorbol 12-myristate 13-acetate (PMA) in THP-1 cells. The analysis was performed on THP-1 cells which expressed MLL-AF9 even after PMA-induced monocyte-macrophage differentiation, as previously reported (10).…”

“…In this study, we analyzed the expression patterns of HOXA4, 5,6,7,9,10,11 and MEIS1 by semiquantitative RT-PCR during the monocyte-macrophage differentiation induced by phorbol 12-myristate 13-acetate (PMA) in THP-1 cells. The analysis was performed on THP-1 cells which expressed MLL-AF9 even after PMA-induced monocyte-macrophage differentiation, as previously reported (10). The results indicate that HOXA4, 7, 10, 11 and MEIS1 gene expression is potentially involved in the differentiation blockage observed in MLL-AF9-induced leukemogenesis.…”

“…We previously showed that the down-regulation of MLL-AF9 expression is not obligatory for monocyte-macrophage maturation in AML-M5 cells carrying t(9;11)(p22;q23). In this study, we analyzed the expression patterns of HOXA4, 5,6,7,9,10 and 11 (defined as 'HOXA-code' genes) and MEIS1 by semiquantitative RT-PCR during the monocytemacrophage differentiation induced by phorbol 12-myristate 13-acetate (PMA) in THP-1 cells carrying t(9;11)(p22;q23) and expressing MLL-AF9. The analyses were performed in THP-1 cells expressing MLL-AF9 even after PMA treatment.…”