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IKAROS and LEUKEMIA

Olsson, Linda LU (2014) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2014:121.
Abstract (Swedish)
Popular Abstract in Swedish

Den vanligaste barncancerformen är akut leukemi, en form av blodcancer som uppstår i immunförsvarets celler och som drabbar cirka 75 barn i Sverige varje år. Även om de flesta av barnen idag botas får en av fem återfall och då minskar överlevnaden drastiskt trots intensiv behandling. Vad det är som gör leukemin mer motståndskraftig när den återkommer vet man ännu inte i detalj. Det är sålunda viktigt att man redan vid diagnostillfället så säkert som möjligt kan förutspå vilka barn som har stor risk för återfall och som av den anledningen ska få mer behandling. Det är även betydelsefullt att identifiera de leukemipatienter som kan botas med mindre aggressiv terapi, för att i görligaste mån minska... (More)
Popular Abstract in Swedish

Den vanligaste barncancerformen är akut leukemi, en form av blodcancer som uppstår i immunförsvarets celler och som drabbar cirka 75 barn i Sverige varje år. Även om de flesta av barnen idag botas får en av fem återfall och då minskar överlevnaden drastiskt trots intensiv behandling. Vad det är som gör leukemin mer motståndskraftig när den återkommer vet man ännu inte i detalj. Det är sålunda viktigt att man redan vid diagnostillfället så säkert som möjligt kan förutspå vilka barn som har stor risk för återfall och som av den anledningen ska få mer behandling. Det är även betydelsefullt att identifiera de leukemipatienter som kan botas med mindre aggressiv terapi, för att i görligaste mån minska biverkningar associerade med cytostatika.



Numera används genetiska analyser för att påvisa förändringar som innebär att patienten ska ha mer eller mindre intensiv behandling, något som medför en mer anpassad behandling. Detta har till stora delar bidragit till den förbättrade överlevnaden av barnleukemi de senaste åren. Det ska dock starkt betonas att många av dem som får återfall inte uppvisar några kända genetiska högrisk-markörer vid diagnostillfället. Av den anledningen är det väsentligt att hitta nya mutationer som framöver kan komma att vara riskgrupperande.



Syftet med mitt avhandlingsarbete har varit att angripa ovanstående frågeställningar genom att kartlägga genetiska förändringar som förekommer i patienter som fått återfall (recidiverat) eller inte svarat på den initiala behandlingen och att studera förekomsten av dessa mutationer i leukemiprov från barn som blivit botade, med målet att finna förändringar som är klart överrepresenterade i de fall som sedermera recidiverar. (Less)
Abstract
Acute lymphoblastic leukemia (ALL) is characterized by an accumulation of immature lymphoid cells in the bone marrow and is the most common cancer type in children. It is an immunophenotypically, morphologically, clinically, and genetically heterogeneous disorder that comprises several distinct subtypes. Proper classification is important because determining the correct subtype plays a vital role for prognostication and treatment strategy. During the last decades, the use of polychemotherapy and implementation of risk stratification based on the presence of certain acquired genetic changes in pediatric B-cell precursor (BCP) ALL have increased the overall survival rates substantially; they are now approaching 90%. This notwithstanding, 20%... (More)
Acute lymphoblastic leukemia (ALL) is characterized by an accumulation of immature lymphoid cells in the bone marrow and is the most common cancer type in children. It is an immunophenotypically, morphologically, clinically, and genetically heterogeneous disorder that comprises several distinct subtypes. Proper classification is important because determining the correct subtype plays a vital role for prognostication and treatment strategy. During the last decades, the use of polychemotherapy and implementation of risk stratification based on the presence of certain acquired genetic changes in pediatric B-cell precursor (BCP) ALL have increased the overall survival rates substantially; they are now approaching 90%. This notwithstanding, 20% of patients still relapse and only half of these survive. A considerable proportion of all relapses lacks the high risk-stratifying genetic changes included in most current ALL treatment protocols. Hence, it is important to identify novel genetic features associated with treatment failure to ensure proper therapy intensity and to detect genes and pathways that in the future can be targeted by specific drugs.



To identify relapse-associated genetic aberrations in pediatric BCP ALL, single nucleotide polymorphism array analyses were performed on uniformly treated patients accrued between 1992 and 2011 from the Lund and Linköping University Hospitals (Article I). In the 191 successfully analyzed cases, deletions of IKZF1 (∆IKZF1) and SPRED1 were shown to be associated with a poor prognosis, with ∆IKZF1 being an independent risk factor for relapse. To ascertain whether ∆IKZF1 is an independent risk factor also in the context of minimal residual disease (MRD) findings, an extended cohort including all 334 Swedish pediatric BCP ALL cases with known IKZF1 status was investigated (Article II). That study confirmed that ∆IKZF1 confers a poor prognosis, revealed that such deletions are particularly common in cases with uninformative cytogenetics, and showed that the prognostic impact of ∆IKZF1 is independent of MRD stratification. However, coexisting genetic changes may play a role in modifying the pathogenetic and/or clinical impact of ∆IKZF1. Therefore, ∆IKZF1-positive cases were investigated further in Article III in order to identify additional, recurrent changes. Furthermore, targeted deep sequencing of all IKZF1 exons in 140 BCP ALL cases was performed, identifying sequence mutations (mutIKZF1) in 5.7%. Of the mutIKZF1-positive cases, one-fourth also harbored ∆IKZF1. In total, 35 cases with IKZF1 abnormalities (abnIKZF1), comprising ∆IKZF1 and/or mutIKZF1, could be analyzed with regard to other genetic anomalies. These analyses showed that CRLF2 rearrangements, caused by deletions of the pseudoautosomal region 1 (PAR1), and JAK2 mutations were significantly overrepresented in abnIKZF1-positive cases and that the presence of PAR1 deletions conferred a poor prognostic impact. Thus, in order to ascertain correctly the clinical ramifications of abnIKZF1 in pediatric BCP ALL, PAR1 deletions should possibly also be screened for. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • professor, PhD Cross, Nicholas, Wessex Regional Genetics Laboratory, Salisbury, Faculty of Medicine, University of Southampton,United Kingdom
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Pediatric acute lymphoblastic leukemia, relapse, risk-stratifying factors, IKZF1, cooperative changes
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2014:121
pages
96 pages
publisher
Division of Clinical Genetics, Lund University
defense location
Belfragesalen, BMC D15, Klinikgatan 32, Lund
defense date
2014-11-22 10:00
ISSN
1652-8220
ISBN
978-91-7619-050-0
language
English
LU publication?
yes
id
670e0e9b-bb83-4e65-8936-649e33e535d4 (old id 4699510)
date added to LUP
2014-10-30 10:54:55
date last changed
2016-09-19 08:44:45
@phdthesis{670e0e9b-bb83-4e65-8936-649e33e535d4,
  abstract     = {Acute lymphoblastic leukemia (ALL) is characterized by an accumulation of immature lymphoid cells in the bone marrow and is the most common cancer type in children. It is an immunophenotypically, morphologically, clinically, and genetically heterogeneous disorder that comprises several distinct subtypes. Proper classification is important because determining the correct subtype plays a vital role for prognostication and treatment strategy. During the last decades, the use of polychemotherapy and implementation of risk stratification based on the presence of certain acquired genetic changes in pediatric B-cell precursor (BCP) ALL have increased the overall survival rates substantially; they are now approaching 90%. This notwithstanding, 20% of patients still relapse and only half of these survive. A considerable proportion of all relapses lacks the high risk-stratifying genetic changes included in most current ALL treatment protocols. Hence, it is important to identify novel genetic features associated with treatment failure to ensure proper therapy intensity and to detect genes and pathways that in the future can be targeted by specific drugs.<br/><br>
<br/><br>
To identify relapse-associated genetic aberrations in pediatric BCP ALL, single nucleotide polymorphism array analyses were performed on uniformly treated patients accrued between 1992 and 2011 from the Lund and Linköping University Hospitals (Article I). In the 191 successfully analyzed cases, deletions of IKZF1 (∆IKZF1) and SPRED1 were shown to be associated with a poor prognosis, with ∆IKZF1 being an independent risk factor for relapse. To ascertain whether ∆IKZF1 is an independent risk factor also in the context of minimal residual disease (MRD) findings, an extended cohort including all 334 Swedish pediatric BCP ALL cases with known IKZF1 status was investigated (Article II). That study confirmed that ∆IKZF1 confers a poor prognosis, revealed that such deletions are particularly common in cases with uninformative cytogenetics, and showed that the prognostic impact of ∆IKZF1 is independent of MRD stratification. However, coexisting genetic changes may play a role in modifying the pathogenetic and/or clinical impact of ∆IKZF1. Therefore, ∆IKZF1-positive cases were investigated further in Article III in order to identify additional, recurrent changes. Furthermore, targeted deep sequencing of all IKZF1 exons in 140 BCP ALL cases was performed, identifying sequence mutations (mutIKZF1) in 5.7%. Of the mutIKZF1-positive cases, one-fourth also harbored ∆IKZF1. In total, 35 cases with IKZF1 abnormalities (abnIKZF1), comprising ∆IKZF1 and/or mutIKZF1, could be analyzed with regard to other genetic anomalies. These analyses showed that CRLF2 rearrangements, caused by deletions of the pseudoautosomal region 1 (PAR1), and JAK2 mutations were significantly overrepresented in abnIKZF1-positive cases and that the presence of PAR1 deletions conferred a poor prognostic impact. Thus, in order to ascertain correctly the clinical ramifications of abnIKZF1 in pediatric BCP ALL, PAR1 deletions should possibly also be screened for.},
  author       = {Olsson, Linda},
  isbn         = {978-91-7619-050-0},
  issn         = {1652-8220},
  keyword      = {Pediatric acute lymphoblastic leukemia,relapse,risk-stratifying factors,IKZF1,cooperative changes},
  language     = {eng},
  pages        = {96},
  publisher    = {Division of Clinical Genetics, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {IKAROS and LEUKEMIA},
  volume       = {2014:121},
  year         = {2014},
}