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Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation.

Bousquet M, Quelen C, Rosati R, Mansat-De Mas V, La Starza R, Bastard C, Lippert E, Talmant P, Lafage-Pochitaloff M, Leroux D, Gervais C, Viguié F, Lai JL, Terre C, Beverlo B, Sambani C, Hagemeijer A, Marynen P, Delsol G, Dastugue N, Mecucci C, Brousset P - J. Exp. Med. (2008)

Bottom Line: In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold).In vitro experiments revealed that miR-125b was able to interfere with primary human CD34(+) cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines.Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity.

View Article: PubMed Central - PubMed

Affiliation: Institut National de Santé et de Recherche Médicale, U563, Centre de Physiopathologie de Toulouse-Purpan, 31300 Toulouse, France.

ABSTRACT
Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34(+) cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity.

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Overexpression of the mature miR-125b and one of its putative pri-microRNA (AK123947) in patients with the t(2;11)(p21;q23), as shown by RQ-PCR. (A) Up-regulation of the mature miR-125b in five AML patients with the translocation (P3, P7, P8, P9, and P10) compared with controls (five cases of AML without the t(2;11) and three BM samples from healthy individuals; P < 0.05). (B) The same results obtained in six MDS patients (P11, P12, P16, P17, P18, and P19). Controls are six MDS patients lacking the t(2;11) and three normal BM samples (P < 0.05). (C) The putative pri-microRNA AK123947 is also up-regulated in the AML patients (P3, P7, P8, and P9) compared with controls (P < 0.05). (D) The same results obtained in MDS patients (P11, P12, P16, P17, and P18; P < 0.05). Horizontal lines indicate mean values.
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fig2: Overexpression of the mature miR-125b and one of its putative pri-microRNA (AK123947) in patients with the t(2;11)(p21;q23), as shown by RQ-PCR. (A) Up-regulation of the mature miR-125b in five AML patients with the translocation (P3, P7, P8, P9, and P10) compared with controls (five cases of AML without the t(2;11) and three BM samples from healthy individuals; P < 0.05). (B) The same results obtained in six MDS patients (P11, P12, P16, P17, P18, and P19). Controls are six MDS patients lacking the t(2;11) and three normal BM samples (P < 0.05). (C) The putative pri-microRNA AK123947 is also up-regulated in the AML patients (P3, P7, P8, and P9) compared with controls (P < 0.05). (D) The same results obtained in MDS patients (P11, P12, P16, P17, and P18; P < 0.05). Horizontal lines indicate mean values.

Mentions: We next tested by quantitative RT-PCR (RQ-PCR) the status of genes/expressed sequence tags located around the breakpoint region (THADA, STS-1, BRCC2, and MTA3) that could be deregulated in these pathologies, but we did not observe significant modifications of their expression (unpublished data). We focused our attention on the three microRNAs (miR-125b-1, let-7a-2, and miR-100) located near the breakpoint area on chromosome 11 (Fig. 1 A). By RQ-PCR, we compared their level of expression in patients with the t(2;11) translocation with six patients with MDS and five patients with AML without the t(2;11) translocation. We also compared the results with three BM samples from healthy individuals. Among the 19 patients, mRNA was available for 6 MDS patients (P11, P12, P16, P17, P18, and P19) and for 5 AML patients (P3, P7, P8, P9, and P10). These experiments showed an elevated expression of the miR-125b (from 6- to 90-fold) in patients with the translocation compared with healthy individuals, or individuals with MDS and AML lacking the t(2;11)(p21;q23) translocation (Fig. 2, A and B). However, the production of the mature miR-125b depends on two loci located on chromosomes 11q23 and 21q21, and the RQ-PCR technique used did not allow discrimination between them. This prompted us to determine which could be the pri-microRNA of miR-125b-1. Fig. 1 A indicates that many mRNAs could be at the origin of miR-125b-1. RQ-PCR confirmed that mature miR-125b was transcribed from chromosome 11 (miR-125b-1 locus), because a strong expression of the mRNA AK123947 located on chromosome 11 was observed in patients with the translocation compared with control cases (Fig. 2, C and D).


Myeloid cell differentiation arrest by miR-125b-1 in myelodysplastic syndrome and acute myeloid leukemia with the t(2;11)(p21;q23) translocation.

Bousquet M, Quelen C, Rosati R, Mansat-De Mas V, La Starza R, Bastard C, Lippert E, Talmant P, Lafage-Pochitaloff M, Leroux D, Gervais C, Viguié F, Lai JL, Terre C, Beverlo B, Sambani C, Hagemeijer A, Marynen P, Delsol G, Dastugue N, Mecucci C, Brousset P - J. Exp. Med. (2008)

Overexpression of the mature miR-125b and one of its putative pri-microRNA (AK123947) in patients with the t(2;11)(p21;q23), as shown by RQ-PCR. (A) Up-regulation of the mature miR-125b in five AML patients with the translocation (P3, P7, P8, P9, and P10) compared with controls (five cases of AML without the t(2;11) and three BM samples from healthy individuals; P < 0.05). (B) The same results obtained in six MDS patients (P11, P12, P16, P17, P18, and P19). Controls are six MDS patients lacking the t(2;11) and three normal BM samples (P < 0.05). (C) The putative pri-microRNA AK123947 is also up-regulated in the AML patients (P3, P7, P8, and P9) compared with controls (P < 0.05). (D) The same results obtained in MDS patients (P11, P12, P16, P17, and P18; P < 0.05). Horizontal lines indicate mean values.
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fig2: Overexpression of the mature miR-125b and one of its putative pri-microRNA (AK123947) in patients with the t(2;11)(p21;q23), as shown by RQ-PCR. (A) Up-regulation of the mature miR-125b in five AML patients with the translocation (P3, P7, P8, P9, and P10) compared with controls (five cases of AML without the t(2;11) and three BM samples from healthy individuals; P < 0.05). (B) The same results obtained in six MDS patients (P11, P12, P16, P17, P18, and P19). Controls are six MDS patients lacking the t(2;11) and three normal BM samples (P < 0.05). (C) The putative pri-microRNA AK123947 is also up-regulated in the AML patients (P3, P7, P8, and P9) compared with controls (P < 0.05). (D) The same results obtained in MDS patients (P11, P12, P16, P17, and P18; P < 0.05). Horizontal lines indicate mean values.
Mentions: We next tested by quantitative RT-PCR (RQ-PCR) the status of genes/expressed sequence tags located around the breakpoint region (THADA, STS-1, BRCC2, and MTA3) that could be deregulated in these pathologies, but we did not observe significant modifications of their expression (unpublished data). We focused our attention on the three microRNAs (miR-125b-1, let-7a-2, and miR-100) located near the breakpoint area on chromosome 11 (Fig. 1 A). By RQ-PCR, we compared their level of expression in patients with the t(2;11) translocation with six patients with MDS and five patients with AML without the t(2;11) translocation. We also compared the results with three BM samples from healthy individuals. Among the 19 patients, mRNA was available for 6 MDS patients (P11, P12, P16, P17, P18, and P19) and for 5 AML patients (P3, P7, P8, P9, and P10). These experiments showed an elevated expression of the miR-125b (from 6- to 90-fold) in patients with the translocation compared with healthy individuals, or individuals with MDS and AML lacking the t(2;11)(p21;q23) translocation (Fig. 2, A and B). However, the production of the mature miR-125b depends on two loci located on chromosomes 11q23 and 21q21, and the RQ-PCR technique used did not allow discrimination between them. This prompted us to determine which could be the pri-microRNA of miR-125b-1. Fig. 1 A indicates that many mRNAs could be at the origin of miR-125b-1. RQ-PCR confirmed that mature miR-125b was transcribed from chromosome 11 (miR-125b-1 locus), because a strong expression of the mRNA AK123947 located on chromosome 11 was observed in patients with the translocation compared with control cases (Fig. 2, C and D).

Bottom Line: In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold).In vitro experiments revealed that miR-125b was able to interfere with primary human CD34(+) cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines.Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity.

View Article: PubMed Central - PubMed

Affiliation: Institut National de Santé et de Recherche Médicale, U563, Centre de Physiopathologie de Toulouse-Purpan, 31300 Toulouse, France.

ABSTRACT
Most chromosomal translocations in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) involve oncogenes that are either up-regulated or form part of new chimeric genes. The t(2;11)(p21;q23) translocation has been cloned in 19 cases of MDS and AML. In addition to this, we have shown that this translocation is associated with a strong up-regulation of miR-125b (from 6- to 90-fold). In vitro experiments revealed that miR-125b was able to interfere with primary human CD34(+) cell differentiation, and also inhibited terminal (monocytic and granulocytic) differentiation in HL60 and NB4 leukemic cell lines. Therefore, miR-125b up-regulation may represent a new mechanism of myeloid cell transformation, and myeloid neoplasms carrying the t(2;11) translocation define a new clinicopathological entity.

Show MeSH
Related in: MedlinePlus