Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23)

Syed Khizer Hasan, Gianluca Barba, Markus Metzler, Mariadomenica Divona, Tiziana Ottone, Laura Cicconi, Brunangelo Falini, Cristina Mecucci, Francesco Lo-Coco

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy-related acute leukemias (t-AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t-AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t-AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL-AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130-32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215-17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non-homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy-related acute leukemia with MLL-AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites.

Original languageEnglish
Pages (from-to)248-254
Number of pages7
JournalGenes Chromosomes and Cancer
Volume53
Issue number3
DOIs
Publication statusPublished - Mar 2014

Fingerprint

Cluster Analysis
Leukemia
Nucleotides
Introns
Biphenotypic Acute Leukemia
Therapeutics
Type II DNA Topoisomerase
Idarubicin
Topoisomerase II Inhibitors
Epirubicin
DNA Cleavage
Gene Rearrangement
Insertional Mutagenesis
Multiplex Polymerase Chain Reaction
DNA Sequence Analysis
DNA Repair

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23). / Hasan, Syed Khizer; Barba, Gianluca; Metzler, Markus; Divona, Mariadomenica; Ottone, Tiziana; Cicconi, Laura; Falini, Brunangelo; Mecucci, Cristina; Lo-Coco, Francesco.

In: Genes Chromosomes and Cancer, Vol. 53, No. 3, 03.2014, p. 248-254.

Research output: Contribution to journalArticle

Hasan, SK, Barba, G, Metzler, M, Divona, M, Ottone, T, Cicconi, L, Falini, B, Mecucci, C & Lo-Coco, F 2014, 'Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23)', Genes Chromosomes and Cancer, vol. 53, no. 3, pp. 248-254. https://doi.org/10.1002/gcc.22135
Hasan, Syed Khizer ; Barba, Gianluca ; Metzler, Markus ; Divona, Mariadomenica ; Ottone, Tiziana ; Cicconi, Laura ; Falini, Brunangelo ; Mecucci, Cristina ; Lo-Coco, Francesco. / Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23). In: Genes Chromosomes and Cancer. 2014 ; Vol. 53, No. 3. pp. 248-254.
@article{e04d2bf158c849ceae165329e594a793,
title = "Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23)",
abstract = "Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy-related acute leukemias (t-AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t-AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t-AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL-AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130-32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215-17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non-homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy-related acute leukemia with MLL-AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites.",
author = "Hasan, {Syed Khizer} and Gianluca Barba and Markus Metzler and Mariadomenica Divona and Tiziana Ottone and Laura Cicconi and Brunangelo Falini and Cristina Mecucci and Francesco Lo-Coco",
year = "2014",
month = "3",
doi = "10.1002/gcc.22135",
language = "English",
volume = "53",
pages = "248--254",
journal = "Genes Chromosomes and Cancer",
issn = "1045-2257",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23)

AU - Hasan, Syed Khizer

AU - Barba, Gianluca

AU - Metzler, Markus

AU - Divona, Mariadomenica

AU - Ottone, Tiziana

AU - Cicconi, Laura

AU - Falini, Brunangelo

AU - Mecucci, Cristina

AU - Lo-Coco, Francesco

PY - 2014/3

Y1 - 2014/3

N2 - Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy-related acute leukemias (t-AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t-AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t-AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL-AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130-32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215-17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non-homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy-related acute leukemia with MLL-AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites.

AB - Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy-related acute leukemias (t-AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t-AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t-AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL-AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130-32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215-17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non-homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy-related acute leukemia with MLL-AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites.

UR - http://www.scopus.com/inward/record.url?scp=84892484623&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892484623&partnerID=8YFLogxK

U2 - 10.1002/gcc.22135

DO - 10.1002/gcc.22135

M3 - Article

C2 - 24310817

AN - SCOPUS:84892484623

VL - 53

SP - 248

EP - 254

JO - Genes Chromosomes and Cancer

JF - Genes Chromosomes and Cancer

SN - 1045-2257

IS - 3

ER -