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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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Identification of the breakpoints on chromosome 11. (A) Mapping of the BAC and fosmid probes on the breakpoint area and positions of the several mRNAs and microRNAs in this region. Vertical arrows show the exact position of the breakpoints for four patients obtained by LDI-PCR. (B) FISH showing chromosome painting of the t(2;11)(p21;q23) translocation in P1. Chromosome 2 is stained in green (biotin-streptavidin-FITC), and chromosome 11 is stained in red (digoxigenin-anti-dig-Rhodamine). (C) FISH with RP11-382J20 (green), as illustrated in A. The second BAC (red) is RP11-142I2 located at 11q23. Note that RP11-382J20 is split (P1). Of note, this BAC is split in 16 out of 19 patients (Table S1, available at http://www.jem.org/cgi/content/full/jem.20080285/DC1). (D) FISH with fosmid G248P85412D12 (green), as illustrated in A, and RP11-391M15 (red) mapping on chromosome 2p21 (P12). This fosmid is split in three patients (Table S1).
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fig1: Identification of the breakpoints on chromosome 11. (A) Mapping of the BAC and fosmid probes on the breakpoint area and positions of the several mRNAs and microRNAs in this region. Vertical arrows show the exact position of the breakpoints for four patients obtained by LDI-PCR. (B) FISH showing chromosome painting of the t(2;11)(p21;q23) translocation in P1. Chromosome 2 is stained in green (biotin-streptavidin-FITC), and chromosome 11 is stained in red (digoxigenin-anti-dig-Rhodamine). (C) FISH with RP11-382J20 (green), as illustrated in A. The second BAC (red) is RP11-142I2 located at 11q23. Note that RP11-382J20 is split (P1). Of note, this BAC is split in 16 out of 19 patients (Table S1, available at http://www.jem.org/cgi/content/full/jem.20080285/DC1). (D) FISH with fosmid G248P85412D12 (green), as illustrated in A, and RP11-391M15 (red) mapping on chromosome 2p21 (P12). This fosmid is split in three patients (Table S1).

Mentions: The t(2;11)(p21;q23) chromosomal translocation was found in 19 patients with AML (n = 10) or MDS (n = 9; Fig. 1 B; and Table S1, available at http://www.jem.org/cgi/content/full/jem.20080285/DC1). The median age of patients was 60 yr. The MDS were classified as refractory cytopenia with multilineage dysplasia, refractory cytopenia with multilineage dysplasia with ring sideroblasts, and refractory anemia with excess blasts. The AMLs were classified in AML with multilineage dysplasia in five patients or in AML evolving from myelodysplasia in three others. In two patients with AML, myelodysplastic signs could not be assessed. We can infer from these morphological data that AMLs with t(2;11) were acute phases of MDS in most patients.


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)

Identification of the breakpoints on chromosome 11. (A) Mapping of the BAC and fosmid probes on the breakpoint area and positions of the several mRNAs and microRNAs in this region. Vertical arrows show the exact position of the breakpoints for four patients obtained by LDI-PCR. (B) FISH showing chromosome painting of the t(2;11)(p21;q23) translocation in P1. Chromosome 2 is stained in green (biotin-streptavidin-FITC), and chromosome 11 is stained in red (digoxigenin-anti-dig-Rhodamine). (C) FISH with RP11-382J20 (green), as illustrated in A. The second BAC (red) is RP11-142I2 located at 11q23. Note that RP11-382J20 is split (P1). Of note, this BAC is split in 16 out of 19 patients (Table S1, available at http://www.jem.org/cgi/content/full/jem.20080285/DC1). (D) FISH with fosmid G248P85412D12 (green), as illustrated in A, and RP11-391M15 (red) mapping on chromosome 2p21 (P12). This fosmid is split in three patients (Table S1).
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fig1: Identification of the breakpoints on chromosome 11. (A) Mapping of the BAC and fosmid probes on the breakpoint area and positions of the several mRNAs and microRNAs in this region. Vertical arrows show the exact position of the breakpoints for four patients obtained by LDI-PCR. (B) FISH showing chromosome painting of the t(2;11)(p21;q23) translocation in P1. Chromosome 2 is stained in green (biotin-streptavidin-FITC), and chromosome 11 is stained in red (digoxigenin-anti-dig-Rhodamine). (C) FISH with RP11-382J20 (green), as illustrated in A. The second BAC (red) is RP11-142I2 located at 11q23. Note that RP11-382J20 is split (P1). Of note, this BAC is split in 16 out of 19 patients (Table S1, available at http://www.jem.org/cgi/content/full/jem.20080285/DC1). (D) FISH with fosmid G248P85412D12 (green), as illustrated in A, and RP11-391M15 (red) mapping on chromosome 2p21 (P12). This fosmid is split in three patients (Table S1).
Mentions: The t(2;11)(p21;q23) chromosomal translocation was found in 19 patients with AML (n = 10) or MDS (n = 9; Fig. 1 B; and Table S1, available at http://www.jem.org/cgi/content/full/jem.20080285/DC1). The median age of patients was 60 yr. The MDS were classified as refractory cytopenia with multilineage dysplasia, refractory cytopenia with multilineage dysplasia with ring sideroblasts, and refractory anemia with excess blasts. The AMLs were classified in AML with multilineage dysplasia in five patients or in AML evolving from myelodysplasia in three others. In two patients with AML, myelodysplastic signs could not be assessed. We can infer from these morphological data that AMLs with t(2;11) were acute phases of MDS in most patients.

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