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

Boer, Judith M.; Veer, Arian van der; Rizopoulos, Dimitris; Fiocco, M.; Sonneveld, Edwin; Groot-Kruseman, Hester A. de; Kuiper, Roland P.; Hoogerbrugge, Peter M.; Horstmann, Martin; Žaliová, Markéta; Palmi, Chiara; Trka, Jan; Froňková, Eva; Emerenciano, Mariana; Pombo‐de‐Oliveira, Maria S.; Młynarski, Wojciech; Szczepański, Tomasz; Nebral, Karin; Attarbaschi, Andishe; Venn, Nicola C.; Sutton, Rosemary; Schwab, Claire; Enshaei, Amir; Vora, Ajay; Stanulla, Martin; Schrappe, Martin; Cazzaniga, Giovanni; Conter, Valentino; Zimmermann, Martin; Moorman, Anthony V.; Pieters, Rob; Boer, Monique L. den

doi:10.1038/leu.2015.199

Cited by 91 publications

(85 citation statements)

References 45 publications

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“…15 Alterations mainly comprise deletions and only rarely sequence alterations. 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.…”

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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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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“…19,20 Although many studies have examined the prognostic relevance of secondary abnormalities (including IKZF1 deletion, ETV6 deletions, RAS pathway mutations) within these two subgroups, no reliable additional biomarkers have emerged. [21][22][23][24][25] In addition, within high hyperdiploidy, many studies have assessed specific trisomies, modal chromosome number and structural abnormalities as additional prognostic markers. Although specific trisomies (+4, +10, +17 and +18) have emerged as clinically relevant biomarkers within particular treatment protocols, they have not proved to be universally applicable.…”

Section: Good-risk Prognostic Genetic Biomarkersmentioning

confidence: 99%

New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia

2016

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“…Germline PAX5 mutations have been implicated in familial B-ALL predisposition [Shah et al, 2013]. The IKZF1 gene , IKAROS family zinc finger 1 (OMIM 603023), located at 7p12.2, is involved in B-cell proliferation and is associated with an unfavorable prognosis in pediatric B-ALL [Boer et al, 2015]. The CDKN2A/B genes (OMIM 600160, 600431), cyclin-dependent kinase inhibitors, are thought to be tumor suppressors.…”

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confidence: 99%

The Genomic Landscape of PAX5, IKZF1, and CDKN2A/B Alterations in B-Cell Precursor Acute Lymphoblastic Leukemia

Sherer²,

Casey³

et al. 2016

Cytogenet Genome Res

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We present a comprehensive comparison of PAX5,IKZF1, and CDKN2A/B abnormalities in 21 B-cell precursor acute lymphoblastic leukemia (B-ALL) patients studied by aCGH and gene-specific FISH assays. In our cohort of B-ALL patients, alterations of IKZF1, PAX5, and CDKN2A/B were detected by aCGH analysis in 43, 52, and 57% of samples, respectively. Deletions of IKZF1 were present in 9 samples, including 5 cases positive for both PAX5 and IKZF1 deletions, implying digenic impairment. Furthermore, all cases with IKZF1 deletions also had additional genomic alterations, including BCR-ABL1 gene fusions, PAX5 deletions, CDKN2A/B deletions, and FLT3 amplification. Deletions of CDKN2A/B represented the most frequent abnormalities in our group of patients. Our study demonstrates the high incidence of PAX5, IKZF1, and CDKN2A/B alterations in B-ALL detected by aCGH analysis. Due to the small size and variability in the deletion breakpoints, FISH studies showed false-negative results in 10, 40, and 28% of the samples tested for the IKZF1,PAX5, and CDKN2A/B gene deletions, respectively. The PAX5 and IKZF1 abnormalities are highly specific to B-ALL and can be used as diagnostic markers. Moreover, IKZF1 alterations frequently coexist with a BCR-ABL gene fusion. Our study revealed multiple additional B-ALL-specific genomic alterations and showed that aCGH is a more sensitive method than FISH, allowing whole genome profiling and identification of aberrations of diagnostic and prognostic significance in patients with B-ALL.

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

Cited by 91 publications

References 45 publications

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

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

New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia

The Genomic Landscape of <b><i>PAX5</i></b>, <b><i>IKZF1</i></b>, and <b><i>CDKN2A/B </i></b>Alterations in B-Cell Precursor Acute Lymphoblastic Leukemia

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