<i>IKZF1</i>(Ikaros) Deletions in<i>BCR-ABL1</i>–Positive Acute Lymphoblastic Leukemia Are Associated With Short Disease-Free Survival and High Rate of Cumulative Incidence of Relapse: A GIMEMA AL WP Report

Martinelli, Giovanni; Iacobucci, Ilaria; Storlazzi, Clelia Tiziana; Vignetti, Marco; Paoloni, Francesca; Cilloni, Daniela; Soverini, Simona; Vitale, Antonella; Chiaretti, Sabina; Cimino, Giuseppe; Papayannidis, Cristina; Paolini, Stefania; Elia, Loredana; Fazi, Paola; Meloni, Giovanna; Amadori, Sergio; Saglio, Giuseppe; Pane, Fabrizio; Baccarani, Michele; Foà, Robin

doi:10.1200/jco.2008.21.6408

Cited by 278 publications

(241 citation statements)

References 27 publications

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“…Although PAX5 alterations are the most frequent genetic abnormality in precursor B-cell ALL [40], the loss of PAX5 is not associated with poor outcomes, possibly because of a lack of deregulation in stem cell-associated genes [41]. In contrast, deletion or sequence mutation of the IKZF1 gene, encoding the early lymphoid transcription factor Ikaros, increases the risk of treatment failure [42][43][44][45]. It appears that when leukemias occur in the earlier phases of lymphocyte development, the prognosis is poorer for childhood ALL, irrespective of whether it is B-or T-cell ALL.…”

Section: Discussionmentioning

confidence: 99%

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

Yang

Hsiao

Chen

et al. 2011

Pediatric Blood & Cancer

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BackgroundThe absence of biallelic TCRγ deletion (ABD) is a characteristic of early thymocyte precursors before V(D)J recombination. The ABD was reported to predict early treatment failure in T‐cell acute lymphoblastic leukemia (ALL). This study aimed to investigate its prognostic value in Taiwanese patients with T‐cell ALL.ProcedureForty‐five children with T‐cell ALL were enrolled from six medical centers in Taiwan. Quantitative DNA polymerase chain reaction (Q‐PCR) was performed to check the status of TCRγ deletion. The threshold for homozygous deletions by Q‐PCR was defined as a fold‐change <0.35.ResultsABD was found in 20 patients [20:45] who had higher incidences of induction failure than those without ABD (P = 0.03; hazard ratio [HR] = 8.13; 95% confidence interval [95% CI] = 1.23–53.77) after multivariate regression analysis. Patents with ABD also had inferior EFS and OS (P = 0.071 and 0.0196, respectively). Multivariate Cox analysis indicated that the association between ABD and overall survival was independent of age and leukocyte count on presentation (P = 0.036; HR = 4.25; 95% CI = 1.10–16.42).ConclusionsThe absence of TCRγ deletion is a predictor of a poor response to induction chemotherapy for pediatric patients with T‐cell ALL in Taiwan. Providing patients with T‐cell ALL and ABD with alternative regimens may be worthwhile to test in future clinical trials. Pediatr Blood Cancer 2012; 58: 846–851. © 2011 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

Yang

Hsiao

Chen

et al. 2011

Pediatric Blood & Cancer

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“…32,33 Similarly, IKZF1 deletions are associated with a very poor outcome and high relapse rate in B-cell ALL. 34,35 Monosomy 7 is known as a recurrent cytogenetic aberration in approximately 10% of adult and 5% of childhood AML cases. 36 Of the seven patients in our study showing loss of IKZF1, two had monosomy 7.…”

Section: Discussionmentioning

confidence: 99%

Deletions of the transcription factor Ikaros in myeloproliferative neoplasms

et al. 2010

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Transformation to acute leukemia is a major complication of myeloproliferative neoplasms (MPNs), however, the genetic changes leading to transformation remain largely unknown. We screened nine patients with post-MPN leukemia for chromosomal aberrations using microarray karyotyping. Deletions on the short arm of chromosome 7 (del7p) emerged as a recurrent defect. We mapped the common deleted region to the IKZF1 gene, which encodes the transcription factor Ikaros. We further examined the frequency of IKZF1 deletions in a total of 29 post-MPN leukemia and 526 MPN patients without transformation and observed a strong association of IKZF1 deletions with post-MPN leukemia in two independent cohorts. Patients with IKZF1 loss showed complex karyotypes, and del7p was a late event in the genetic evolution of the MPN clone. IKZF1 deletions were observed in both undifferentiated and differentiated myeloid cell types, indicating that IKZF1 loss does not cause differentiation arrest but rather renders progenitors susceptible to transformation, most likely through chromosomal instability. Induced Ikzf1 haploinsufficiency in primary murine progenitors resulted in elevated Stat5 phosphorylation and increased cytokine-dependent growth, suggesting that reduced expression of IKZF1 is sufficient to perturb growth regulation. Thus, IKZF1 loss is an important step in the leukemic transformation of a subpopulation of MPN patients.

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“…As a result, the recurrent DNA copy number anomalies in IKZF1 gene and the deletion of exons 4 to 7 with breakpoints occurring in introns 3 and 7 on chromosome 7p12 were identified. 13 The details were shown in Supplementary Figure 1.…”

Section: Immunophenotypingmentioning

confidence: 99%

Newly diagnosed acute lymphoblastic leukemia in China (I): abnormal genetic patterns in 1346 childhood and adult cases and their comparison with the reports from Western countries

et al. 2012

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It has been generally acknowledged that the diagnosis, treatment and prognosis evaluation of leukemia largely rely on an adequate identification of genetic abnormalities. A systemic analysis of genetic aberrations was performed in a cohort of 1346 patients with newly diagnosed acute lymphoblastic leukemia (ALL) in China. The pediatric patients had higher incidence of hyperdiploidy and t(12;21) (p13;q22)/ETV6 --RUNX1 than adults (Po0.0001); in contrast, the occurrence of Ph and Ik6 variant of IKZF1 gene was much more frequent in adult patients (all Po0.0001). In B-ALL, the existence of Ik6 and that of BCR --ABL were statistically correlated (Po0.0001). In comparison with Western cohorts, the incidence of t(9;22) (q34;q11)/BCR --ABL (14.60%) in B-ALL and HOX11 expression in T-ALL (25.24%) seemed to be much higher in our group, while the incidence of t(12;21) (p13;q22)/ETV6 --RUNX1 (15.34%) seemed to be lower in Chinese pediatric patients. The occurrence of hyperdiploidy was much lower either in pediatric (10.61% vs 20 --38%) or adult patients (2.36% vs 6.77 --12%) in our study than in Western reports. In addition, the frequencies of HOX11L2 in adult patients were much higher in our cohort than in Western countries (20.69% vs 4 --11%). In general, it seems that Chinese ALL patients bear more adverse prognostic factors than their Western counterparts do.

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IKZF1(Ikaros) Deletions inBCR-ABL1–Positive Acute Lymphoblastic Leukemia Are Associated With Short Disease-Free Survival and High Rate of Cumulative Incidence of Relapse: A GIMEMA AL WP Report

Abstract: We conclude that IKZF1 deletions are likely to be a genomic alteration that significantly affects the prognosis of Ph-positive ALL in adults.

Cited by 278 publications

References 27 publications

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

Deletions of the transcription factor Ikaros in myeloproliferative neoplasms

Newly diagnosed acute lymphoblastic leukemia in China (I): abnormal genetic patterns in 1346 childhood and adult cases and their comparison with the reports from Western countries

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