Frequency and prognostic implications of JAK 1-3 aberrations in Down syndrome acute lymphoblastic and myeloid leukemia

Blink, Marjolein; Buitenkamp, Trudy; Heuvel‐Eibrink, Marry M. van den; Oorschot, Astrid A Danen-van; Haas, Valérie de; Reinhardt, Dirk; Klusmann, Jan‐Henning; Zimmermann, Martin; Devidas, Meenakshi; Carroll, Andrew J.; Basso, Giuseppe; Pession, Andrea; Hasle, Henrik; Pieters, Rob; Rabin, K. R.; Izraeli, Shai; Zwaan, C. Michel

doi:10.1038/leu.2011.86

Cited by 20 publications

(17 citation statements)

References 9 publications

(29 reference statements)

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“…JAK2 R683-activating mutations were found in 5/34 (15%) of the DCOG DS ALL patients as previously reported. 30 The incidence of JAK2 R683 mutations was higher in the UK cohort (8/20, 40%) as previously reported. 16 …”

Section: Mutation Analysissupporting

confidence: 72%

“…8,29,30 Multiplex ligation-dependent probe amplification (MLPA) MLPA was used in both DCOG and UK cases for detection and validation of aberrations in B-cell development and differentiation genes found by array-CGH and to further define IKZF1 deletions into different splice variants. MLPA analysis was performed using the SALSA MLPA kit P335-A3 ALL-IKZF1, which contains probes for selected B-cell development and differentiation genes, and the SALSA MLPA kit P202-A1 IKZF1, which contains an increased density of probes for IKZF1 (MRC-Holland, Amsterdam, The Netherlands).…”

Section: Mutation Analysismentioning

confidence: 99%

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

et al. 2012

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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.

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Section: Mutation Analysissupporting

confidence: 72%

Section: Mutation Analysismentioning

confidence: 99%

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

et al. 2012

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“…Some of these data have been previously reported. 20,24,25 However, several study groups contributed new unpublished data.…”

Section: Patientsmentioning

confidence: 99%

“…2,7,18,19 Recently, genetic abnormalities such as JAK2 mutations 20 and CRLF2 rearrangements have been identified in both DS and non-DS-ALL. 3,4,[20][21][22][23][24][25][26][27] Activating JAK2 R683 mutations were found in ;18% of DS-ALL patients. 20,24 Rearrangements of CRLF2 occurred in ;60% of DS-ALL patients and in fewer than 10% of non-DS-ALL patients.…”

Section: Introductionmentioning

confidence: 99%

“…3,4,[20][21][22][23][24][25][26][27] Activating JAK2 R683 mutations were found in ;18% of DS-ALL patients. 20,24 Rearrangements of CRLF2 occurred in ;60% of DS-ALL patients and in fewer than 10% of non-DS-ALL patients. 3,4,23 In almost all instances, JAK2 (or rarely JAK1 or IL7R) mutations were associated with CRLF2 gene rearrangements, suggesting a model by which CRLF2 overexpression results in JAK-STAT activation and proliferation of the leukemic clone.…”

Section: Introductionmentioning

confidence: 99%

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Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group

Buitenkamp

Izraeli

Zimmermann³

et al. 2014

Blood

194

292

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Key Points• Although the risk of ALL relapse is significantly higher in children with DS, goodprognosis subgroups have been identified. • Patients with DS-ALL have higher treatment-related mortality throughout the treatment period independent of the therapeutic regimen.Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Münster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% 6 2% vs 15% 6 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% 6 1% vs 2.0% 6 <1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% 6 2% vs 81% 6 2%, P < .0001) and overall survival (74% 6 2% vs 89% 6 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] 5 0.58, P 5 .002), white blood cell (WBC) count <10 3 10 9 /L (HR 5 0.60, P 5 .005), and ETV6-RUNX1 (HR 5 0.14, P 5 .006) for EFS and age (HR 5 0.48, P < .001), ETV6-RUNX1 (HR 5 0.1, P 5 .016) and high hyperdiploidy (HeH) (HR 5 0.29, P 5 .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DSALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups. (Blood. 2014; 123(1):70-77)

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Gene alterations involving the CRLF2‐JAK pathway and recurrent gene deletions in Down syndrome‐associated acute lymphoblastic leukemia in Japan

Hanada

Terui

Ikeda

et al. 2014

Genes Chromosomes & Cancer

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In Western countries, gene alterations involving the CRLF2‐JAK signaling pathway are identified in approximately 50–60% of patients with Down syndrome‐associated acute lymphoblastic leukemia (DS‐ALL), and this pathway is considered a potential therapeutic target. The frequency of BTG1 deletions in DS‐ALL is controversial. IKZF1 deletions, found in 20–30% of DS‐ALL patients, are associated with a poor outcome and EBF1 deletions are very rare (∼2%). We analyzed 38 patients to determine the frequencies and clinical implications of CRLF2‐JAK pathway genetic alterations and recurrent gene deletions in Japanese DS‐ALL patients. We confirmed a high incidence of P2RY8‐CRLF2 (29%) and JAK2 mutations (16%), though the frequency of P2RY8‐CRLF2 was slightly lower than that in Western countries (∼50%). BTG1 deletions were common in our cohort (25%). IKZF1 deletions were detected in 25% of patients and associated with shorter overall survival (OS). EBF1 deletions were found at an unexpectedly high frequency (16%), and at a significantly higher level in P2RY8‐CRLF2‐positive patients than in P2RY8‐CRLF2‐negative patients (44% vs. 4%, P = 0.015). Deletions of CDKN2A/B and PAX5 were common in P2RY8‐CRLF2‐negative patients (48 and 39%, respectively) but not in P2RY8‐CRLF2‐positive patients (11% each). Associations between these genetic alterations and clinical characteristics were not observed except for inferior OS in patients with IKZF1 deletions. These results suggest that differences exist between the genetic profiles of DS‐ALL patients in Japan and in Western countries, and that P2RY8‐CRLF2 and EBF1 deletions may cooperate in leukemogenesis in a subset of Japanese DS‐ALL patients. © 2014 Wiley Periodicals, Inc.

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Frequency and prognostic implications of JAK 1-3 aberrations in Down syndrome acute lymphoblastic and myeloid leukemia

Cited by 20 publications

References 9 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

Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group

Gene alterations involving the CRLF2‐JAK pathway and recurrent gene deletions in Down syndrome‐associated acute lymphoblastic leukemia in Japan

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