Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial

Ensor, Hannah; Schwab, Claire; Russell, Lisa J.; Richards, Sue; Morrison, Heather; Mašić, Dino; Jones, Lisa; Kinsey, Sally; Vora, Ajay; Mitchell, Christopoher D; Harrison, Christine J.; Moorman, Anthony V.

doi:10.1182/blood-2010-07-297135

Cited by 134 publications

(152 citation statements)

References 17 publications

Supporting

Mentioning

136

Contrasting

Unclassified

Order By: Relevance

“…30 The incidence of JAK2 R683 mutations was higher in the UK cohort (8/20, 40%) as previously reported. 16 …”

Section: Mutation Analysismentioning

confidence: 99%

“…8,16 Briefly, we used a break-apart FISH probe to identify CRLF2 involvement. A break-apart probe to P2RY8 was designed to map the centromeric breakpoint of the deletion in patients with loss of the centromeric signal indicating deletion within the pseudoautosomal region centromeric of CRLF2.…”

Section: Patients and Patient Samplesmentioning

confidence: 99%

“…6,[10][11][12] Mutations of JAK2 and rearrangements of CRLF2 are found in o10% and up to 15% of high-risk non-DS ALL patients, respectively. 8,[12][13][14][15][16] Deletions in B-cell development and differentiation genes, including IKZF1, TCF3, EBF1, PAX5 and VPREB1, have recently been described in DS and non-DS ALL. [17][18][19][20] The prognostic significance of abnormalities of these genes in DS ALL is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations

et al. 2012

View full text Add to dashboard Cite

Children with Down's syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL) and have a low frequency of established genetic aberrations. We aimed to determine which genetic abnormalities are involved in DS ALL. We studied the frequency and prognostic value of deletions in B-cell development genes and aberrations of janus kinase 2 (JAK2) and cytokine receptor-like factor 2 (CRLF2) using array-comparative genomic hybridization, and multiplex ligation-dependent probe amplification in a population-based cohort of 34 Dutch Childhood Oncology Group DS ALL samples. A population-based cohort of 88 DS samples from the UK trials was used to validate survival estimates for IKZF1 and CRLF2 abnormalities. In total, 50% of DS ALL patients had X1 deletion in the B-cell development genes: PAX5 (12%), VPREB1 (18%) and IKZF1 (35%). JAK2 was mutated in 15% of patients, genomic CRLF2 rearrangements in 62%. Outcome was significantly worse in patients with IKZF1 deletions (6-year eventfree survival (EFS) 45 ± 16% vs 95 ± 4%; P ¼ 0.002), which was confirmed in the validation cohort (6-year EFS 21 ± 12% vs 58 ± 11%; P ¼ 0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P ¼ 0.001). Neither CRLF2 nor JAK2 were predictors for worse prognosis. If confirmed in prospective series, IKZF1 deletions may be used for risk-group stratification in DS ALL.

show abstract

“…30 The incidence of JAK2 R683 mutations was higher in the UK cohort (8/20, 40%) as previously reported. 16 …”

Section: Mutation Analysismentioning

confidence: 99%

Section: Patients and Patient Samplesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Moreover, CRLF2 aberrations were not proven to bear significant prognostic value in children with ALL treated on UK protocols. 13 Here, we present data on the incidence and prognostic impact of CRLF2 over-expression, specifically P2RY8-CRLF2 fusion, at diagnosis in 464 Italian BCP-ALL children treated with the protocol of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) and Berlin-Frankfurt-Munster (BFM) group ('AIEOP-BFM ALL2000 protocol') and the potential impact of P2RY8-CRLF2 fusion within MRD-based subgroups.…”

Section: Introductionmentioning

confidence: 99%

“…There is a need to identify which of the recently discovered genetic alterations have the potential to improve patient stratification 2 as well as for the development of targeted therapeutic approaches. [3][4][5] In a subset of BCP-ALL patients without known chromosomal aberrations, two genomic abnormalities have been reported that involve Ikaros (IKZF1) 6,7 and cytokine receptor-like factor 2 (CRLF2) [8][9][10][11][12][13] genes. The latter abnormality includes small deletions within the pseudoautosomal region (PAR1) of the sex chromosomes as well as the translocation of this region to the IGH@ locus on chromosome 14.…”

Section: Introductionmentioning

confidence: 99%

Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia

et al. 2012

View full text Add to dashboard Cite

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has achieved an 80% cure rate as a result of a risk-adapted therapy largely based on minimal residual disease (MRD) monitoring. However, relapse is still the most frequent adverse event, occurring mainly in the patients with intermediate MRD levels (intermediate risk, IR), emphasizing the need for new prognostic markers. We analyzed the prognostic impact of cytokine receptor-like factor 2 (CRLF2) over-expression and P2RY8-CRLF2 fusion in 464 BCP-ALL patients (not affected by Down syndrome and BCR-ABL negative) enrolled in the AIEOP-BFM ALL2000 study in Italy. In 22/464 (4.7%) samples, RQ-PCR showed CRLF2 over-expression (X20 times higher than the overall median). P2RY8-CRLF2 fusion was detected in 22/365 (6%) cases, with 10/22 cases also showing CRLF2 over-expression. P2RY8-CRLF2 fusion was the most relevant prognostic factor independent of CRLF2 over-expression with a threefold increase in risk of relapse. Significantly, the cumulative incidence of relapse of the P2RY8-CRLF2 þ patients in the IR group was high (61.1% ± 12.9 vs 17.6% ± 2.6, Po0.0001), similar to high-risk patients in AIEOP-BFM ALL2000 study. These results were confirmed in a cohort of patients treated in Germany. In conclusion, P2RY8-CRLF2 identifies a subset of BCP-ALL patients currently stratified as IR that could be considered for treatment intensification.

show abstract

Acute lymphoblastic leukaemia

Andersson¹,

Moorman²,

Harrison³

et al. 2016

The Genetic Basis of Haematological Cancers

Self Cite

View full text Add to dashboard Cite

Acute lymphoblastic leukaemia (ALL) is seen in both children and adults, but its incidence peaks between ages 2 and 5 years. The causation of ALL is considered to be multi-factorial, including exogenous or endogenous exposures, genetic susceptibility, and chance. The survival rate of paediatric ALL has improved to approximately 90% in recent trials with risk stratification by biologic features of leukaemic cells and response to therapy, therapy modification based on patient pharmacodynamics and pharmacogenomics, and improved supportive care. However, innovative approaches are needed to further improve survival while reducing adverse effects. While most children can be cured, the prognosis of infants and adults with ALL remains poor. Recent genomewide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic alterations and sequence mutations that contribute to leukaemogenesis, define new ALL subtypes, influence responsiveness to treatment, and may provide novel prognostic markers and therapeutic targets for personalized medicine. Epidemiology ALL, like cancer in general, is likely to arise from interactions between exogenous or endogenous exposures, genetic (inherited) susceptibility, and chance (figure 1). These factors account for the approximately 1 in 2000 risk of childhood (0-15 years) ALL. The challenge is to identify the relevant exposures and inherited genetic variants and to decipher

show abstract

Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial

Cited by 134 publications

References 17 publications

Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations

Outcome in children with Down's syndrome and acute lymphoblastic leukemia: role of IKZF1 deletions and CRLF2 aberrations

Poor prognosis for P2RY8-CRLF2 fusion but not for CRLF2 over-expression in children with intermediate risk B-cell precursor acute lymphoblastic leukemia

Acute lymphoblastic leukaemia

Contact Info

Product

Resources

About