TY  - JOUR
AU  - Klampfl, Thorsten
AU  - Milosević, Jelena D.
AU  - Puda, Ana
AU  - Schoenegger, Andreas
AU  - Bagienski, Klaudia
AU  - Berg, Tiina
AU  - Harutyunyan, Ashot S.
AU  - Gisslinger, Bettina
AU  - Rumi, Elisa
AU  - Malcovati, Luca
AU  - Pietra, Daniela
AU  - Elena, Chiara
AU  - Della Porta, Matteo Giovanni
AU  - Pieri, Lisa
AU  - Guglielmelli, Paola
AU  - Bock, Christoph
AU  - Doubek, Michael
AU  - Dvorakova, Dana
AU  - Suvajdžić, Nada
AU  - Tomin, Dragica
AU  - Tošić, Nataša
AU  - Racil, Zdenek
AU  - Steurer, Michael
AU  - Pavlović, Sonja
AU  - Vannucchi, Alessandro M.
AU  - Cazzola, Mario
AU  - Gisslinger, Heinz
AU  - Kralovics, Robert
PY  - 2013
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/673
AB  - Exome sequencing of primary tumors identifies complex somatic mutation patterns. Assignment of relevance of individual somatic mutations is difficult and poses the next challenge for interpretation of next generation sequencing data. Here we present an approach how exome sequencing in combination with SNP microarray data may identify targets of chromosomal aberrations in myeloid malignancies. The rationale of this approach is that hotspots of chromosomal aberrations might also harbor point mutations in the target genes of deletions, gains or uniparental disomies (UPDs). Chromosome 11 is a frequent target of lesions in myeloid malignancies. Therefore, we studied chromosome 11 in a total of 813 samples from 773 individual patients with different myeloid malignancies by SNP microarrays and complemented the data with exome sequencing in selected cases exhibiting chromosome 11 defects. We found gains, losses and UPDs of chromosome 11 in 52 of the 813 samples (6.4%). Chromosome 11q UPDs frequently associated with mutations of CBL. In one patient the 11qUPD amplified somatic mutations in both CBL and the DNA repair gene DDB1. A duplication within MLL exon 3 was detected in another patient with 11qUPD. We identified several common deleted regions (CDR) on chromosome 11. One of the CDRs associated with de novo acute myeloid leukemia (P=0.013). One patient with a deletion at the LMO2 locus harbored an additional point mutation on the other allele indicating that LMO2 might be a tumor suppressor frequently targeted by 11p deletions. Our chromosome-centered analysis indicates that chromosome 11 contains a number of tumor suppressor genes and that the role of this chromosome in myeloid malignancies is more complex than previously recognized.
PB  - Public Library Science, San Francisco
T2  - PLoS One
T1  - Complex Patterns of Chromosome 11 Aberrations in Myeloid Malignancies Target CBL, MLL, DDB1 and LMO2
IS  - 10
VL  - 8
DO  - 10.1371/journal.pone.0077819
ER  - 

@article{
author = "Klampfl, Thorsten and Milosević, Jelena D. and Puda, Ana and Schoenegger, Andreas and Bagienski, Klaudia and Berg, Tiina and Harutyunyan, Ashot S. and Gisslinger, Bettina and Rumi, Elisa and Malcovati, Luca and Pietra, Daniela and Elena, Chiara and Della Porta, Matteo Giovanni and Pieri, Lisa and Guglielmelli, Paola and Bock, Christoph and Doubek, Michael and Dvorakova, Dana and Suvajdžić, Nada and Tomin, Dragica and Tošić, Nataša and Racil, Zdenek and Steurer, Michael and Pavlović, Sonja and Vannucchi, Alessandro M. and Cazzola, Mario and Gisslinger, Heinz and Kralovics, Robert",
year = "2013",
abstract = "Exome sequencing of primary tumors identifies complex somatic mutation patterns. Assignment of relevance of individual somatic mutations is difficult and poses the next challenge for interpretation of next generation sequencing data. Here we present an approach how exome sequencing in combination with SNP microarray data may identify targets of chromosomal aberrations in myeloid malignancies. The rationale of this approach is that hotspots of chromosomal aberrations might also harbor point mutations in the target genes of deletions, gains or uniparental disomies (UPDs). Chromosome 11 is a frequent target of lesions in myeloid malignancies. Therefore, we studied chromosome 11 in a total of 813 samples from 773 individual patients with different myeloid malignancies by SNP microarrays and complemented the data with exome sequencing in selected cases exhibiting chromosome 11 defects. We found gains, losses and UPDs of chromosome 11 in 52 of the 813 samples (6.4%). Chromosome 11q UPDs frequently associated with mutations of CBL. In one patient the 11qUPD amplified somatic mutations in both CBL and the DNA repair gene DDB1. A duplication within MLL exon 3 was detected in another patient with 11qUPD. We identified several common deleted regions (CDR) on chromosome 11. One of the CDRs associated with de novo acute myeloid leukemia (P=0.013). One patient with a deletion at the LMO2 locus harbored an additional point mutation on the other allele indicating that LMO2 might be a tumor suppressor frequently targeted by 11p deletions. Our chromosome-centered analysis indicates that chromosome 11 contains a number of tumor suppressor genes and that the role of this chromosome in myeloid malignancies is more complex than previously recognized.",
publisher = "Public Library Science, San Francisco",
journal = "PLoS One",
title = "Complex Patterns of Chromosome 11 Aberrations in Myeloid Malignancies Target CBL, MLL, DDB1 and LMO2",
number = "10",
volume = "8",
doi = "10.1371/journal.pone.0077819"
}

Klampfl, T., Milosević, J. D., Puda, A., Schoenegger, A., Bagienski, K., Berg, T., Harutyunyan, A. S., Gisslinger, B., Rumi, E., Malcovati, L., Pietra, D., Elena, C., Della Porta, M. G., Pieri, L., Guglielmelli, P., Bock, C., Doubek, M., Dvorakova, D., Suvajdžić, N., Tomin, D., Tošić, N., Racil, Z., Steurer, M., Pavlović, S., Vannucchi, A. M., Cazzola, M., Gisslinger, H.,& Kralovics, R.. (2013). Complex Patterns of Chromosome 11 Aberrations in Myeloid Malignancies Target CBL, MLL, DDB1 and LMO2. in PLoS One
Public Library Science, San Francisco., 8(10).
https://doi.org/10.1371/journal.pone.0077819

Klampfl T, Milosević JD, Puda A, Schoenegger A, Bagienski K, Berg T, Harutyunyan AS, Gisslinger B, Rumi E, Malcovati L, Pietra D, Elena C, Della Porta MG, Pieri L, Guglielmelli P, Bock C, Doubek M, Dvorakova D, Suvajdžić N, Tomin D, Tošić N, Racil Z, Steurer M, Pavlović S, Vannucchi AM, Cazzola M, Gisslinger H, Kralovics R. Complex Patterns of Chromosome 11 Aberrations in Myeloid Malignancies Target CBL, MLL, DDB1 and LMO2. in PLoS One. 2013;8(10).
doi:10.1371/journal.pone.0077819 .

Klampfl, Thorsten, Milosević, Jelena D., Puda, Ana, Schoenegger, Andreas, Bagienski, Klaudia, Berg, Tiina, Harutyunyan, Ashot S., Gisslinger, Bettina, Rumi, Elisa, Malcovati, Luca, Pietra, Daniela, Elena, Chiara, Della Porta, Matteo Giovanni, Pieri, Lisa, Guglielmelli, Paola, Bock, Christoph, Doubek, Michael, Dvorakova, Dana, Suvajdžić, Nada, Tomin, Dragica, Tošić, Nataša, Racil, Zdenek, Steurer, Michael, Pavlović, Sonja, Vannucchi, Alessandro M., Cazzola, Mario, Gisslinger, Heinz, Kralovics, Robert, "Complex Patterns of Chromosome 11 Aberrations in Myeloid Malignancies Target CBL, MLL, DDB1 and LMO2" in PLoS One, 8, no. 10 (2013),
https://doi.org/10.1371/journal.pone.0077819 . .

TY  - JOUR
AU  - Milosević, Jelena D.
AU  - Puda, Ana
AU  - Malcovati, Luca
AU  - Berg, Tiina
AU  - Hofbauer, Michael
AU  - Stukalov, Alexey
AU  - Klampfl, Thorsten
AU  - Harutyunyan, Ashot S.
AU  - Gisslinger, Heinz
AU  - Gisslinger, Bettina
AU  - Burjanivova, Tatiana
AU  - Rumi, Elisa
AU  - Pietra, Daniela
AU  - Elena, Chiara
AU  - Vannucchi, Alessandro M.
AU  - Doubek, Michael
AU  - Dvorakova, Dana
AU  - Robesova, Blanka
AU  - Wieser, Rotraud
AU  - Koller, Elisabeth
AU  - Suvajdžić, Nada
AU  - Tomin, Dragica
AU  - Tošić, Nataša
AU  - Colinge, Jacques
AU  - Racil, Zdenek
AU  - Steurer, Michael
AU  - Pavlović, Sonja
AU  - Cazzola, Mario
AU  - Kralovics, Robert
PY  - 2012
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/590
AB  - The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% +/- 9.4% vs. 35.4% +/- 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.335.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms. Am. J. Hematol., 2012.
PB  - Wiley, Hoboken
T2  - American Journal of Hematology
T1  - Clinical significance of genetic aberrations in secondary acute myeloid leukemia
EP  - 1016
IS  - 11
SP  - 1010
VL  - 87
DO  - 10.1002/ajh.23309
ER  - 

@article{
author = "Milosević, Jelena D. and Puda, Ana and Malcovati, Luca and Berg, Tiina and Hofbauer, Michael and Stukalov, Alexey and Klampfl, Thorsten and Harutyunyan, Ashot S. and Gisslinger, Heinz and Gisslinger, Bettina and Burjanivova, Tatiana and Rumi, Elisa and Pietra, Daniela and Elena, Chiara and Vannucchi, Alessandro M. and Doubek, Michael and Dvorakova, Dana and Robesova, Blanka and Wieser, Rotraud and Koller, Elisabeth and Suvajdžić, Nada and Tomin, Dragica and Tošić, Nataša and Colinge, Jacques and Racil, Zdenek and Steurer, Michael and Pavlović, Sonja and Cazzola, Mario and Kralovics, Robert",
year = "2012",
abstract = "The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% +/- 9.4% vs. 35.4% +/- 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.335.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms. Am. J. Hematol., 2012.",
publisher = "Wiley, Hoboken",
journal = "American Journal of Hematology",
title = "Clinical significance of genetic aberrations in secondary acute myeloid leukemia",
pages = "1016-1010",
number = "11",
volume = "87",
doi = "10.1002/ajh.23309"
}

Milosević, J. D., Puda, A., Malcovati, L., Berg, T., Hofbauer, M., Stukalov, A., Klampfl, T., Harutyunyan, A. S., Gisslinger, H., Gisslinger, B., Burjanivova, T., Rumi, E., Pietra, D., Elena, C., Vannucchi, A. M., Doubek, M., Dvorakova, D., Robesova, B., Wieser, R., Koller, E., Suvajdžić, N., Tomin, D., Tošić, N., Colinge, J., Racil, Z., Steurer, M., Pavlović, S., Cazzola, M.,& Kralovics, R.. (2012). Clinical significance of genetic aberrations in secondary acute myeloid leukemia. in American Journal of Hematology
Wiley, Hoboken., 87(11), 1010-1016.
https://doi.org/10.1002/ajh.23309

Milosević JD, Puda A, Malcovati L, Berg T, Hofbauer M, Stukalov A, Klampfl T, Harutyunyan AS, Gisslinger H, Gisslinger B, Burjanivova T, Rumi E, Pietra D, Elena C, Vannucchi AM, Doubek M, Dvorakova D, Robesova B, Wieser R, Koller E, Suvajdžić N, Tomin D, Tošić N, Colinge J, Racil Z, Steurer M, Pavlović S, Cazzola M, Kralovics R. Clinical significance of genetic aberrations in secondary acute myeloid leukemia. in American Journal of Hematology. 2012;87(11):1010-1016.
doi:10.1002/ajh.23309 .

Milosević, Jelena D., Puda, Ana, Malcovati, Luca, Berg, Tiina, Hofbauer, Michael, Stukalov, Alexey, Klampfl, Thorsten, Harutyunyan, Ashot S., Gisslinger, Heinz, Gisslinger, Bettina, Burjanivova, Tatiana, Rumi, Elisa, Pietra, Daniela, Elena, Chiara, Vannucchi, Alessandro M., Doubek, Michael, Dvorakova, Dana, Robesova, Blanka, Wieser, Rotraud, Koller, Elisabeth, Suvajdžić, Nada, Tomin, Dragica, Tošić, Nataša, Colinge, Jacques, Racil, Zdenek, Steurer, Michael, Pavlović, Sonja, Cazzola, Mario, Kralovics, Robert, "Clinical significance of genetic aberrations in secondary acute myeloid leukemia" in American Journal of Hematology, 87, no. 11 (2012):1010-1016,
https://doi.org/10.1002/ajh.23309 . .