IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951

Clappier, Emmanuelle; Grardel, Nathalie; Bâkkus, Marleen; Rapion, Jérôme; Moerloose, Barbara De; Kastner, Philippe; Caye, Aurélie; Vivent, Jocelyne; Costa, V.; Ferster, Alina; Lutz, Patrick; Mazingue, Françoise; Millot, Frédéric; Plantaz, Dominique; Plat, Geneviève; Plouvier, Emmanuel; Poirée, Maryline; Sirvent, Nicolas; Uyttebroeck, Anne; Yakouben, Karima; Girard, Sandrine; Dastugue, Nicole; Suciu, Stefan; Benoît, Yves; Bertrand, Yves; Cavé, Hélène

doi:10.1038/leu.2015.134

Cited by 93 publications

(108 citation statements)

References 29 publications

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“…Deletions in the IKZF1 gene encoding the B-cell transcription factor IKAROS have been linked to an unfavorable clinical outcome of BCP-ALL in different treatment protocols, including recent protocols with risk stratification guided by minimal residual disease monitoring. [3][4][5][6][7][8][9][10][11] The IKZF1 gene located on chromosome band 7p12.2 consists of 8 exons. Exons 2 to 8 contain the protein-coding sequence of IKAROS (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study

et al. 2015

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Deletions in IKZF1 are found in ~15% of children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). There is strong evidence for the poor prognosis of IKZF1 deletions affecting exons 4-7 and exons 1-8, but evidence for the remaining 33% of cases harboring other variants of IKZF1 deletions is lacking. In an international multicenter study we analyzed the prognostic value of these rare variants in a case-control design. Each IKZF1-deleted case was matched to three IKZF1 wild-type controls based on cytogenetic subtype, treatment protocol, risk stratification arm, white blood cell count and age. Hazard ratios for the prognostic impact of rare IKZF1 deletions on event-free survival were calculated by matched pair Cox regression. Matched pair analysis for all 134 cases with rare IKZF1 deletions together revealed a poor prognosis (P<0.001) that was evident in each risk stratification arm. Rare variant types with the most unfavorable event-free survival were DEL 2-7 (P=0.03), DEL 2-8 (P=0.002) and DEL-Other (P<0.001). The prognosis of each type of rare variant was equal or worse compared with the well-known major DEL 4-7 and DEL 1-8 IKZF1 deletion variants. We therefore conclude that all variants of rare IKZF1 deletions are associated with an unfavorable prognosis in pediatric BCP-ALL.

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Section: Introductionmentioning

confidence: 99%

Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study

et al. 2015

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“…16, 17, 18 Irrespective of the type of IKZF1 alteration, they prevail in poor responding cases in major treatment protocols. 5, 11, 17, 19, 20, 21, 22, 23 They are a hallmark of high-risk BCP ALL, especially those, which carry a BCR-ABL1 and other cytokine- and kinase-activating fusions, including IGH-CRLF2 and P2RY8-CRLF2. 11, 24 The common characteristic of such cases is a gene expression signature that resembles that of genuine BCR-ABL1 -positive cases and which are, therefore, also referred to as either ' BCR-ABL1 -like' or 'Ph-like'.…”

Section: Introductionmentioning

confidence: 99%

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

Vesely¹,

Frech²,

Eckert

et al. 2016

Leukemia

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Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1’s critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.

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“…Also, recent studies have shown: (1) deletions or mutations of IKZF1 gene correlate with poor prognosis in other subtypes of pre-B ALL, thus providing evidence that IKAROS protein is an important tumor suppressor in pre-B ALL, (2) IKZF1 alterations have been reported in pre-B ALL carrying BCR-ABL1 rearrangement and have been associated with poor treatment outcome, (3) occurrence of IKZF1 aberrations in association with other genetic alterations such as JAK mutations and translocations involving chemokine receptor like factor 2 (CRLF2) in childhood ALL, and (4) IKZF1 alterations in B-cell ALL lead to induction of multiple genes associated with proliferation and treatment resistance suggesting identification of new therapeutic targets for HR disease [101,105,107]. Recently, there have been controversial reports on the benefit of intensifying conventional maintenance chemotherapy by giving vincristine and glucocorticoid pulse therapies in patients with IKZF1 deleted ALL [111,112].…”

Section: Birinapantmentioning

confidence: 99%

Cytogenetics, Molecular Genetics and Epigenetics and Their Impact on The Management of Acute Lymphoblastic Leukemia

Wk¹,

Dridi²,

Ka³

2017

J Mol Genet Med

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The recent improvements in the outcomes of patients with acute lymphoblastic leukemia reflect the progress in the field of diagnostics and the achievements in therapeutic interventions. In particular, the availability of more advanced technology in the cytogenetic and molecular laboratories has resulted in the stratification of patients into specific risk groups and thus several novel agents as well as targeted therapies have been introduced. Additionally, precision medicine will be applicable in the near future and thus the recent developments will facilitate the provision of safer modalities of therapy that may ultimately yield not only higher responses but also improved survival rates.This review represents a recent update on the role of various cytogenetic assays and molecular techniques in patients with acute lymphoblastic leukemia. It is composed of a number of sections including: history of cytogenetics, disease etiology and pathophysiology, utilization of various cytogenetic assays diagnostically, disease-specific cytogenetic and molecular abnormalities, common disease genetic subtypes, prognosis and risk stratification, refractory and relapsed disease, novel therapies, precision medicine and drug repurposing.

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IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951

Cited by 93 publications

References 29 publications

Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study

Prognostic value of rare IKZF1 deletion in childhood B-cell precursor acute lymphoblastic leukemia: an international collaborative study

Genomic and transcriptional landscape of P2RY8-CRLF2-positive childhood acute lymphoblastic leukemia

Cytogenetics, Molecular Genetics and Epigenetics and Their Impact on The Management of Acute Lymphoblastic Leukemia

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