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Genetic Characterization of Pediatric T-cell Acute Lymphoblastic Leukemia

Karrman, Kristina LU (2014) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2014:120.
Abstract
The aim of my thesis has been to characterize genetically pediatric T-cell acute lymphoblastic leukemia (T-ALL).

Articles I and II focus on molecular characterization of translocations involving T-cell receptor (TCR) loci. These types of aberration are characteristic for T-ALL and have previously proved pivotal in the identification of genes implicated in leukemogenesis. The translocation t(12;14)(p13;q11) was shown to result in overexpression of CCND2. The t(12;14) is the first neoplasia-associated translocation shown to result in overexpression of CCND2 and the first example of a targeted deregulation of a member of the cyclin-encoding gene family in T-ALL. Cyclin D proteins are crucial to the cell cycle machinery and hence... (More)
The aim of my thesis has been to characterize genetically pediatric T-cell acute lymphoblastic leukemia (T-ALL).

Articles I and II focus on molecular characterization of translocations involving T-cell receptor (TCR) loci. These types of aberration are characteristic for T-ALL and have previously proved pivotal in the identification of genes implicated in leukemogenesis. The translocation t(12;14)(p13;q11) was shown to result in overexpression of CCND2. The t(12;14) is the first neoplasia-associated translocation shown to result in overexpression of CCND2 and the first example of a targeted deregulation of a member of the cyclin-encoding gene family in T-ALL. Cyclin D proteins are crucial to the cell cycle machinery and hence potential oncogenes. The second translocation cloned, t(X;7)(q22;q34), had not previously been reported in a neoplastic disorder. Breakpoint analysis revealed IRS4 as a novel translocation partner to a TCR locus, resulting in deregulated IRS4 expression, both at the gene and protein level. IRS4 plays an important part in several intracellular signalling cascades, including PI3K-AKT, known to be activated in T-ALL. In a subsequent work, I showed that IRS4 can also be targeted by alternative mechanisms in T-ALL, apart from TCR translocations, namely by mutations (Article IV).

In Article III, clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a large, population-based Nordic series of 285 pediatric T-ALLs. Survival analyses revealed a correlation between rare TCR translocations and inferior outcome, an association that awaits confirmation in a separate study.

Finally, I used several different techniques – fluorescence in situ hybridization, single nucleotide polymorphism (SNP) array, and deep sequencing of 75 selected candidate genes – to characterize co-operative genetic aberrations in a consecutive series of paediatric T-ALL (Article V). One common change identified by SNP array was segemtal uniparental isodisomy (sUPID). This aberration was seen in 44% of the investigated cases, with most being sUPID9p that always were associated with homozygous CDKN2A deletions, with a heterozygous deletion occurring prior to the sUPID9p in all instances. Among the 75 genes investigated by deep sequencing, 14 were mutated in 28 cases. The genes targeted are involved in signalling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse, showing that such mutations also can be secondary events. These findings support a multistep leukemogenic process in pediatric T-ALL.

In summary, through different approaches and by various methods, the articles included in this thesis have deciphered genetic aberrations in pediatric T-ALL, contributing to a better understanding of leukemogenesis. (Less)
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author
supervisor
opponent
  • Speleman, Frank, Ghent, Belgium
organization
publishing date
type
Thesis
publication status
published
subject
keywords
leukmia, genetic characterization, pediatric
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2014:120
pages
84 pages
publisher
Division of Clinical Genetics, Lund University
defense location
Belfragesalen, BMC D15, Klinikgatan 32, Lund
defense date
2014-11-14 09:30
ISSN
1652-8220
ISBN
978-91-7619-049-4
language
English
LU publication?
yes
id
ecf79aa4-5a19-434c-a4ae-c0bce0d29e01 (old id 4698007)
date added to LUP
2014-10-20 13:49:17
date last changed
2016-09-19 08:44:49
@phdthesis{ecf79aa4-5a19-434c-a4ae-c0bce0d29e01,
  abstract     = {The aim of my thesis has been to characterize genetically pediatric T-cell acute lymphoblastic leukemia (T-ALL). <br/><br>
Articles I and II focus on molecular characterization of translocations involving T-cell receptor (TCR) loci. These types of aberration are characteristic for T-ALL and have previously proved pivotal in the identification of genes implicated in leukemogenesis. The translocation t(12;14)(p13;q11) was shown to result in overexpression of CCND2. The t(12;14) is the first neoplasia-associated translocation shown to result in overexpression of CCND2 and the first example of a targeted deregulation of a member of the cyclin-encoding gene family in T-ALL. Cyclin D proteins are crucial to the cell cycle machinery and hence potential oncogenes. The second translocation cloned, t(X;7)(q22;q34), had not previously been reported in a neoplastic disorder. Breakpoint analysis revealed IRS4 as a novel translocation partner to a TCR locus, resulting in deregulated IRS4 expression, both at the gene and protein level. IRS4 plays an important part in several intracellular signalling cascades, including PI3K-AKT, known to be activated in T-ALL. In a subsequent work, I showed that IRS4 can also be targeted by alternative mechanisms in T-ALL, apart from TCR translocations, namely by mutations (Article IV). <br/><br>
In Article III, clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a large, population-based Nordic series of 285 pediatric T-ALLs. Survival analyses revealed a correlation between rare TCR translocations and inferior outcome, an association that awaits confirmation in a separate study. <br/><br>
Finally, I used several different techniques – fluorescence in situ hybridization, single nucleotide polymorphism (SNP) array, and deep sequencing of 75 selected candidate genes – to characterize co-operative genetic aberrations in a consecutive series of paediatric T-ALL (Article V). One common change identified by SNP array was segemtal uniparental isodisomy (sUPID). This aberration was seen in 44% of the investigated cases, with most being sUPID9p that always were associated with homozygous CDKN2A deletions, with a heterozygous deletion occurring prior to the sUPID9p in all instances. Among the 75 genes investigated by deep sequencing, 14 were mutated in 28 cases. The genes targeted are involved in signalling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse, showing that such mutations also can be secondary events. These findings support a multistep leukemogenic process in pediatric T-ALL. <br/><br>
In summary, through different approaches and by various methods, the articles included in this thesis have deciphered genetic aberrations in pediatric T-ALL, contributing to a better understanding of leukemogenesis.},
  author       = {Karrman, Kristina},
  isbn         = {978-91-7619-049-4},
  issn         = {1652-8220},
  keyword      = {leukmia,genetic characterization,pediatric},
  language     = {eng},
  pages        = {84},
  publisher    = {Division of Clinical Genetics, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Genetic Characterization of Pediatric T-cell Acute Lymphoblastic Leukemia},
  volume       = {2014:120},
  year         = {2014},
}