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

Children with Down Syndrome (DS) have an increased risk of developing leukemia, including both acute myeloid (ML-DS) and acute lymphoblastic leukemia (DS ALL).1 These leukemias differ in clinical characteristics and biology from leukemias in non-DS children. ML-DS is characterized by a low diagnostic white blood cell (WBC) count, young age, FAB M7 morphology, excellent clinical outcome with survival rates of >90% and a high sensitivity to chemotherapy in vivo and in-vitro.1, 2 ML-DS is often preceded by transient leukemia (TL) in newborns, which in most cases resolves spontaneously. Approximately 20% of TL patients subsequently develop ML-DS.2 Both the TL and ML-DS blasts are characterized by mutations in the GATA-1 gene, a hematopoietic transcription factor, which result in a truncated protein GATA1s.3 Because these mutations occur both in TL and ML-DS, additional genetic abnormalities are needed in the progression from TL to ML-DS

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

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 ≥1 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 event-free survival (EFS) 45 ± 16% vs 95 ± 4%; P=0.002), which was confirmed in the validation cohort (6-year EFS 21 ± 12% vs 58 ± 11%; P=0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P=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

Outcome in children with Down\u27s syndrome and acute lymphoblastic leukemia: role of <em>IKZF1</em> deletions and <em>CRLF2 </em>aberrations

Children with Down\u27s 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 &gt;= 1 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 event-free survival (EFS) 45 +/- 16% vs 95 +/- 4%; P = 0.002), which was confirmed in the validation cohort (6-year EFS 21 +/- 12% vs 58 +/- 11%; P = 0.002). This IKZF1 deletion was a strong independent predictor for outcome (hazard ratio EFS 3.05; P = 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. Leukemia (2012) 26, 2204-2211; doi:10.1038/leu.2012.8