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  - Puda, Ana
AU  - Milosević, Jelena D.
AU  - Berg, Tiina
AU  - Klampfl, Thorsten
AU  - Harutyunyan, Ashot S.
AU  - Gisslinger, Bettina
AU  - Rumi, Elisa
AU  - Pietra, Daniela
AU  - Malcovati, Luca
AU  - Elena, Chiara
AU  - Doubek, Michael
AU  - Steurer, Michael
AU  - Tošić, Nataša
AU  - Pavlović, Sonja
AU  - Guglielmelli, Paola
AU  - Pieri, Lisa
AU  - Vannucchi, Alessandro M.
AU  - Gisslinger, Heinz
AU  - Cazzola, Mario
AU  - Kralovics, Robert
PY  - 2012
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/601
AB  - Chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) have an inherent tendency to progress to acute myeloid leukemia (AML). Using high-resolution SNP microarrays, we studied a total of 517 MPN and MDS patients in different disease stages, including 77 AML cases with previous history of MPN (N = 46) or MDS (N = 31). Frequent chromosomal deletions of variable sizes were detected, allowing the mapping of putative tumor suppressor genes involved in the leukemic transformation process. We detected frequent deletions on the short arm of chromosome 6 (del6p). The common deleted region on 6p mapped to a 1.1-Mb region and contained only the JARID2 genemember of the polycomb repressive complex 2 (PRC2). When we compared the frequency of del6p between chronic and leukemic phase, we observed a strong association of del6p with leukemic transformation (P = 0.0033). Subsequently, analysis of deletion profiles of other PRC2 members revealed frequent losses of genes such as EZH2, AEBP2, and SUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses of JARID2 and AEBP2. We observed frequent codeletion of AEBP2 and ETV6, and similarly, SUZ12 and NF1. Using next generation exome sequencing of 40 patients, we identified only one somatic mutation in the PRC2 complex member SUZ12. As the frequency of point mutations in PRC2 members was found to be low, deletions were the main type of lesions targeting PRC2 complex members. Our study suggests an essential role of the PRC2 complex in the leukemic transformation of chronic myeloid disorders. Am. J. Hematol. 2012.
PB  - Wiley, Hoboken
T2  - American Journal of Hematology
T1  - Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies
EP  - 250
IS  - 3
SP  - 245
VL  - 87
DO  - 10.1002/ajh.22257
ER  - 

@article{
author = "Puda, Ana and Milosević, Jelena D. and Berg, Tiina and Klampfl, Thorsten and Harutyunyan, Ashot S. and Gisslinger, Bettina and Rumi, Elisa and Pietra, Daniela and Malcovati, Luca and Elena, Chiara and Doubek, Michael and Steurer, Michael and Tošić, Nataša and Pavlović, Sonja and Guglielmelli, Paola and Pieri, Lisa and Vannucchi, Alessandro M. and Gisslinger, Heinz and Cazzola, Mario and Kralovics, Robert",
year = "2012",
abstract = "Chronic myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) have an inherent tendency to progress to acute myeloid leukemia (AML). Using high-resolution SNP microarrays, we studied a total of 517 MPN and MDS patients in different disease stages, including 77 AML cases with previous history of MPN (N = 46) or MDS (N = 31). Frequent chromosomal deletions of variable sizes were detected, allowing the mapping of putative tumor suppressor genes involved in the leukemic transformation process. We detected frequent deletions on the short arm of chromosome 6 (del6p). The common deleted region on 6p mapped to a 1.1-Mb region and contained only the JARID2 genemember of the polycomb repressive complex 2 (PRC2). When we compared the frequency of del6p between chronic and leukemic phase, we observed a strong association of del6p with leukemic transformation (P = 0.0033). Subsequently, analysis of deletion profiles of other PRC2 members revealed frequent losses of genes such as EZH2, AEBP2, and SUZ12; however, the deletions targeting these genes were large. We also identified two patients with homozygous losses of JARID2 and AEBP2. We observed frequent codeletion of AEBP2 and ETV6, and similarly, SUZ12 and NF1. Using next generation exome sequencing of 40 patients, we identified only one somatic mutation in the PRC2 complex member SUZ12. As the frequency of point mutations in PRC2 members was found to be low, deletions were the main type of lesions targeting PRC2 complex members. Our study suggests an essential role of the PRC2 complex in the leukemic transformation of chronic myeloid disorders. Am. J. Hematol. 2012.",
publisher = "Wiley, Hoboken",
journal = "American Journal of Hematology",
title = "Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies",
pages = "250-245",
number = "3",
volume = "87",
doi = "10.1002/ajh.22257"
}

Puda, A., Milosević, J. D., Berg, T., Klampfl, T., Harutyunyan, A. S., Gisslinger, B., Rumi, E., Pietra, D., Malcovati, L., Elena, C., Doubek, M., Steurer, M., Tošić, N., Pavlović, S., Guglielmelli, P., Pieri, L., Vannucchi, A. M., Gisslinger, H., Cazzola, M.,& Kralovics, R.. (2012). Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies. in American Journal of Hematology
Wiley, Hoboken., 87(3), 245-250.
https://doi.org/10.1002/ajh.22257

Puda A, Milosević JD, Berg T, Klampfl T, Harutyunyan AS, Gisslinger B, Rumi E, Pietra D, Malcovati L, Elena C, Doubek M, Steurer M, Tošić N, Pavlović S, Guglielmelli P, Pieri L, Vannucchi AM, Gisslinger H, Cazzola M, Kralovics R. Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies. in American Journal of Hematology. 2012;87(3):245-250.
doi:10.1002/ajh.22257 .

Puda, Ana, Milosević, Jelena D., Berg, Tiina, Klampfl, Thorsten, Harutyunyan, Ashot S., Gisslinger, Bettina, Rumi, Elisa, Pietra, Daniela, Malcovati, Luca, Elena, Chiara, Doubek, Michael, Steurer, Michael, Tošić, Nataša, Pavlović, Sonja, Guglielmelli, Paola, Pieri, Lisa, Vannucchi, Alessandro M., Gisslinger, Heinz, Cazzola, Mario, Kralovics, Robert, "Frequent deletions of JARID2 in leukemic transformation of chronic myeloid malignancies" in American Journal of Hematology, 87, no. 3 (2012):245-250,
https://doi.org/10.1002/ajh.22257 . .