Nondisjunction of chromosomes leading to hyperdiploid childhood B-cell precursor acute lymphoblastic leukemia is an early event during leukemogenesis

Panzer-Grümayer, E. Renate; Fasching, Karin; Panzer, Simon; Hettinger, Klaudia; Schimrigk, К.; Stöckler‐Ipsiroglu, Sylvia; Haas, Oskar A.

doi:10.1182/blood-2002-01-0144

Cited by 83 publications

(77 citation statements)

References 13 publications

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“…It then becomes clear that both structural chromosome changes and mutated RTK-RAS genes are secondary to the high hyperdiploid pattern. Considering that high hyperdiploid cells have been detected already at birth in children who subsequently developed high hyperdiploid ALL, 32,33 these results indicate that structural chromosome abnormalities and FLT3, KRAS, NRAS and…”

Section: Discussionmentioning

confidence: 80%

Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations

et al. 2010

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Although childhood high hyperdiploid acute lymphoblastic leukemia is associated with a favorable outcome, 20% of patients still relapse. It is important to identify these patients already at diagnosis to ensure proper risk stratification. We have investigated 11 paired diagnostic and relapse samples with single nucleotide polymorphism array and mutation analyses of FLT3, KRAS, NRAS and PTPN11 in order to identify changes associated with relapse and to ascertain the genetic evolution patterns. Structural changes, mainly cryptic hemizygous deletions, were significantly more common at relapse (Po0.05). No single aberration was linked to relapse, but four deletions, involving IKZF1, PAX5, CDKN2A/B or AK3, were recurrent. On the basis of the genetic relationship between the paired samples, three groups were delineated: (1) identical genetic changes at diagnosis and relapse (2 of 11 cases), (2) clonal evolution with all changes at diagnosis being present at relapse (2 of 11) and (3) clonal evolution with some changes conserved, lost or gained (7 of 11), suggesting the presence of a preleukemic clone. This ancestral clone was characterized by numerical changes only, with structural changes and RTK-RAS mutations being secondary to the high hyperdiploid pattern.

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Section: Discussionmentioning

confidence: 80%

Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations

et al. 2010

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“…This number of cells was detected in earlier studies on BCP ALL. [5][6][7]9,10 Despite this optimal sensitivity the molecular target was present at birth just in 1 of the 16 cases (Figure 1, sample no. 185).…”

Section: Resultsmentioning

confidence: 99%

“…6,7 Controls included peripheral blood (PB) from healthy donors, thymocytes from 2 young children undergoing cardiac surgery, and Guthrie cards from healthy age-matched anonymous newborns.…”

Section: Methodsmentioning

confidence: 99%

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Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin

Fischer

Mann

Konrad

et al. 2007

Blood

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Childhood T-cell precursor acute lymphoblastic leukemia (TCP ALL) is an aggressive disease with a presumably short latency that differs in many biologic respects from B-cell precursor (BCP) ALL. We therefore addressed the issue of in utero origin of this particular type of leukemia by tracing oncogenic mutations and clone-specific molecular markers back to birth. These markers included various first-and second-hit genetic alterations (TCRD-LMO2 breakpoint regions, n ‫؍‬ 2; TAL1 deletions, n ‫؍‬ 3; Notch1 mutations, n ‫؍‬ 1) and nononcogenic T-cell receptor rearrangements (n ‫؍‬ 13) that were derived from leukemias of 16 children who were 1.5 to 11.2 years old at diagnosis of leukemia. Despite highly sensitive polymerase chain reaction (PCR) approaches (1 cell with a specific marker among 100 000 normal cells), we identified the leukemic clone in the neonatal blood spots in only 1 young child. These data suggest that in contrast to BCP ALL most TCP ALL cases are initiated after birth. (Blood. 2007;110:3036-3038)

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“…However, considering that the hyperdiploid clone may already be present at birth but that there is a latency period of several years before overt leukemia (Panzer-Grü mayer et al, 2002;Maia et al, 2003Maia et al, , 2004, it seems unlikely that the tri-and tetrasomies alone are sufficient for leukemogenesis. Furthermore, it has been shown that a single abnormal mitosis underlies all chromosomal gains in most cases, indicating that the cell giving rise to the hyperdiploid clone harbored other genetic abnormalities, inducing the aberrant cell division and/or allowing it to survive such a drastic and sud-den aneuploidy (Onodera et al, 1992;Paulsson et al, 2003Paulsson et al, , 2005.…”

Section: Introductionmentioning

confidence: 99%

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

Paulsson

Horvat

Strömbeck

et al. 2007

Genes Chromosomes & Cancer

101

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Although it has been suggested that mutations of the FLT3, NRAS, KRAS, and PTPN11 genes are particularly frequent in high hyperdiploid (>50 chromosomes) pediatric acute lymphoblastic leukemias (ALLs), this has as yet not been confirmed in a large patient cohort. Furthermore, it is unknown whether mutations of these genes coexist in hyperdiploid cases. We performed mutation analyses of FLT3, NRAS, KRAS, and PTPN11 in a consecutive series of 78 high hyperdiploid ALLs. Twenty-six (33%) of the cases harbored a mutation, comprising six activating point mutations and one internal tandem duplication of FLT3 (7/78 cases; 9.0%), eight codon 12, 13, or 61 NRAS mutations (8/78 cases; 10%), five codon 12 or 13 KRAS mutations (5/78 cases, 6.4%), and seven exon 3 or 13 PTPN11 mutations (7/78 cases; 9.0%). No association was seen between the presence of a mutation in FLT3, NRAS, KRAS, or PTPN11 and gender, age, white blood cell count, or relapse, suggesting that they do not confer a negative prognostic impact. Only one case harbored mutations in two different genes, suggesting that mutations of these four genes are generally mutually exclusive. In total, one third of the cases harbored a FLT3, NRAS, KRAS, or PTPN11 mutation, identifying the RTK-RAS signaling pathway as a potential target for novel therapies of high hyperdiploid pediatric ALLs. V V C 2007 Wiley-Liss, Inc.

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Nondisjunction of chromosomes leading to hyperdiploid childhood B-cell precursor acute lymphoblastic leukemia is an early event during leukemogenesis

Cited by 83 publications

References 13 publications

Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations

Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations

Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

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