Deletion of the Ink4-locus (the p16ink4a, p14ARF and p15ink4b genes) predicts relapse in children with ALL treated according to the Nordic protocols NOPHO-86 and NOPHO-92

Moreno, TM Calero; Gustafsson, Göran; Garwicz, Stanislaw; Grandér, Dan; Jonmundsson, GK; Frost, Britt‐Marie; Mäkipernaa, Anne; Rasool, Omid; Savolainen, E.–R.; Schmiegelow, Kjeld; Soderhall, S; Vettenranta, Kim; Wesenberg, Finn; Einhorn, Stefan; Heyman, Mats

doi:10.1038/sj.leu.2402697

Cited by 40 publications

(11 citation statements)

References 36 publications

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“…We did not find an association between clinical outcome and extensively studied loci such as CDKN2A/B 32,33 or PAX5 status, despite the finding that PAX5 alterations were the most common lesions in the B-cell–differentiation pathway in both cohorts. PAX5 alterations may be important in establishing the leukemic clone, whereas alterations of IKZF1 may also contribute to resistance to chemotherapy.…”

Section: Discussioncontrasting

confidence: 89%

Deletion ofIKZF1and Prognosis in Acute Lymphoblastic Leukemia

Su²,

et al. 2009

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Background Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. Methods We studied a cohort of 221 children with high-risk B-cell–progenitor ALL with the use of single-nucleotide–polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1–positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell–progenitor ALL. Results More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell–lineage genes, and it was similar to the signature of BCR-ABL1–positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion. Conclusions Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell–progenitor ALL.

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Section: Discussioncontrasting

confidence: 89%

Deletion ofIKZF1and Prognosis in Acute Lymphoblastic Leukemia

Su²,

et al. 2009

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“…CDKN2A deletion was described to be associated with adverse clinical features, higher WBC counts, and leukemic cell burden in previous reports, but the prognostic impact of CDKN2A deletions as well as the status of homozygous deletion has been controversial . In the present study, we did not find an association between CDKN2A/2B deletion and the relapse or survival rate of our patients.…”

Section: Discussioncontrasting

confidence: 79%

Clinical and biological relevance of genetic alterations in pediatric T‐cell acute lymphoblastic leukemia in Taiwan

Yeh

Liang

Liu

et al. 2018

Pediatric Blood & Cancer

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Background: The leukemogenesis of T-cell acute lymphoblastic leukemia (T-ALL) involves multistep processes of genetic alterations. We aimed to determine the genetic alterations including common fusion transcripts, overexpression of T-cell transcription factor oncogenes, and deletion or mutation of targeted genes in pediatric T-ALL in Taiwan as well as their impact on outcomes in those treated with the Taiwan Pediatric Oncology Group-ALL-2002 protocol. Procedure: Between 1995 and 2015, bone marrow samples obtained from 102 children aged <18 years consecutively diagnosed with T-ALL were examined. Thirty-two genetic alterations were examined by reverse transcription polymerase chain reaction (PCR) assays-PCR-based assaysfollowed by direct sequencing, real time quantitative PCR with TaqMan assays, or multiplex ligase probe amplification.Results: TAL1 overexpression, CDKN2A/2B deletions, and NOTCH1 mutation were the most frequent aberrations while none had NF1, SUZ12 deletion, JAK1 or JAK2 mutations, or NUP214-ABL1 fusion in our cohort. The most frequent cooperating occurrence of genetic alterations included CDKN2A/2B and MTAP, MTAP and CDKN2B, LEF1 and PTPN2, and HOX11L2 and PHF6 mutation/deletion. NOTCH1 mutations conferred a favorable overall survival, whereas SIL-TAL1 fusion, TAL overexpression, LEF1 deletion, and PHF6 deletion/mutation were associated with an inferior outcome. By multivariate analysis, PHF6 mutation/deletion was the only independent predictor for inferior overall survival. Conclusions:The present study showed that the frequencies of genetic alterations in Taiwanese children with T-ALL differed considerably from those reported in Western countries. PHF6 mutation/deletion was an independently adverse predictor.

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“…In our BCP‐ALL patients, the 9p21 deletion was less frequent than previously reported (Mirebeau et al , 2006; Kuiper et al , 2007; Mullighan et al , 2007), being found in only two patients (patients 9 and 23). Although CDKN2A has been identified as a tumour suppressor gene, its role in leukaemia development and relapse still remains controversial (Calero Moreno et al , 2002; Mirebeau et al , 2006).…”

Section: Resultsmentioning

confidence: 99%

Array‐CGH reveals hidden gene dose changes in children with acute lymphoblastic leukaemia and a normal or failed karyotype by G‐banding

Kuchinskaya¹,

Heyman

Nordgren³

et al. 2008

Br J Haematol

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SummaryA tiling path 33K BAC array was used to study 28 children with acute lymphoblastic leukaemia (ALL) who had normal or failed G-banded karyotypes. Twenty-two patients (79%) had a total of 135 copy number alterations (CNA) (69 gains and 66 losses); most of these patients showed CNA that were below the resolution of G-banding. Molecular cytogenetic and array comparative genomic hybridization results enabled the division of B-precursor ALL patients into five groups: high hyperdiploidy, intrachromosomal amplification of 21q, ETV6/RUNX1 rearrangement, others and no CNA. Apart from a shared deletion of 9p21.3, T-ALL patients had additional small CNA, with no region in common.

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Deletion of the Ink4-locus (the p16ink4a, p14ARF and p15ink4b genes) predicts relapse in children with ALL treated according to the Nordic protocols NOPHO-86 and NOPHO-92

Cited by 40 publications

References 36 publications

Deletion ofIKZF1and Prognosis in Acute Lymphoblastic Leukemia

Deletion ofIKZF1and Prognosis in Acute Lymphoblastic Leukemia

Clinical and biological relevance of genetic alterations in pediatric T‐cell acute lymphoblastic leukemia in Taiwan

Array‐CGH reveals hidden gene dose changes in children with acute lymphoblastic leukaemia and a normal or failed karyotype by G‐banding

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