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

Abstract

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.

What is the relevance of Ikaros gene deletions as a prognostic marker in pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia?

“…[2][3][4][5][6] Indeed, IKZF1 deletions are rare in T-ALL (about 5%), 7 very frequent in Philadelphia chromosome-positive ALL (about 80%) 8 and frequent in patients with Down syndrome and ALL (reported incidence, 35%). 9 The most frequent IKZF1 alterations identified in ALL patients were deletions encompassing the whole gene or involving only some exons. 5,[7][8][9][10][11][12][13][14][15] All these deletions cause the loss of IKZF1 activity.…”

“…9 The most frequent IKZF1 alterations identified in ALL patients were deletions encompassing the whole gene or involving only some exons. 5,[7][8][9][10][11][12][13][14][15] All these deletions cause the loss of IKZF1 activity.…”

“…IKZF1 deletions were shown to be related to poor outcome in pediatric ALL patients, 5,[7][8][9][10][11][12][13][14][15] but their prognostic impact could be different in specific subgroups. The potential benefit of the early identification of a new prognostic marker should be assessed within the subgroup of patients who are not at high risk due to other features and evaluated in a homogeneous cohort of cases.…”

Ikzf1 Deletions Are Independent Prognostic Factor in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

“…После этого возник большой интерес к дан-ной проблематике, и делеции в гене IKZF1 были опи-саны не только при ВП-ОЛЛ у детей и взрослых. Было показано, что они выявляются у подавляющего боль-шинства больных Ph-позитивным ОЛЛ [6,15,20], а также более чем в половине случаев лимфоидного бластного криза при хроническом миелоидном лейко-зе [15,21], в 40 % случаев при BCR-ABL1-подобном профиле экспрессии генов [22] и примерно у трети больных ОЛЛ и болезнью Дауна [23]. Во всех этих случаях делеции IKZF1 являются независимым про-гностическим фактором, связанным с неблагоприят-ным прогнозом заболевания.…”

Clinically defining and managing high-risk pediatric patients with acute lymphoblastic leukemia

“…41,47 IKZF1 alterations are found more commonly in patients meeting NCI high-risk criteria, those with Phϩ and Ph-like disease, and in patients with Down's syndrome. 39,48,49 Response factors…”