Constitutive Function of the Ikaros Transcription Factor in Primary Leukemia Cells from Pediatric Newly Diagnosed High-Risk and Relapsed B-precursor ALL Patients

Uckun, Fatih M.; Ma, Hong; Ishkhanian, Rita; Arellano, Martha; Shahidzadeh, Anoush; Termuhlen, Amanda; Gaynon, Paul S.; Qazi, Sanjive

doi:10.1371/journal.pone.0080732

Cited by 6 publications

(7 citation statements)

References 26 publications

(42 reference statements)

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“…In this context, we suggest that the function of Ikaros was not affected by the expression of Ik6 and Ik8. This result is in accordance with data reported by other authors, who demonstrates that the function and expression of Ikaros were not decrease by IKZF1 deletions in ALL blasts [ 22 ].…”

Section: Discussionsupporting

confidence: 94%

“…The long isoforms (Ik1, Ik3A and Ik2) were expressed more frequently in our patients in contrast to other populations reported that express both short and long isoforms in B-ALL cases and only short isoforms in the T-ALL patients [ 6 ]. Much like other authors [ 6 , 20 – 22 ], we observed a great heterogeneity in the expression of all Ikaros transcripts in the ALL-children studied.…”

Section: Discussionsupporting

confidence: 87%

“…Considering that several patients showed mixed expression profiles of Ikaros isoforms, and some of them did not have relapse despite expressed DNI, it is possible that the Ikaros function in patients Ik6+ and/or Ik8+ might be compensated by the expression of other Ikaros isoforms [ 22 ]. The functional and biological significance of the DNI (Ik6 and Ik8) was not evaluated in this study.…”

Section: Discussionmentioning

confidence: 99%

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Expression of Ik6 and Ik8 Isoforms and Their Association with Relapse and Death in Mexican Children with Acute Lymphoblastic Leukemia

et al. 2015

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Expression of the 6 and 8 dominant-negative Ikaros isoforms in pediatric patients with acute lymphoblastic leukemia has been associated with a high risk of relapse and death; due to these isoforms disrupting the differentiation and proliferation of lymphoid cells. The aim of this study was to know the frequency of Ik6 and Ik8 in 113 Mexican ALL-children treated within the National Popular Medical Insurance Program to determine whether there was an association with relapse-free survival, event-free survival and overall survival, and to assess its usefulness in the initial stratification of patients. The expression of these isoforms was analyzed using specific primer sets and nested RT-PCR. The detected transcripts were classified according to the isoforms’s sizes reported. A non-expected band of 300 bp from one patient was analyzed by sequencing. Twenty-six patients expressed Ik6 and/or Ik8 and one of them expressed a variant of Ik8 denominated Ik8-deleted. Although the presence of them was not statistically associated with lower relapse free survival (p = 0.432), event free survival (p = 0.667) or overall survival (p = 0.531), inferior overall survival was observed in patients that expressed these isoforms and showed high or standard risk by age and white blood-cell count at diagnosis. Of the 26 patients Ik6+ and/or Ik8+, 14 did not present adverse events; from them 6 were exclusively Ik6+ and/or Ik8+, and 8 were positive for the other Ikaros isoforms (Ik1, Ik2, Ik5, Ik3A, Ik4, Ik4A, Ik7). In the patients studied, the expression of Ik6 and Ik8 did not constitute an independent prognostic factor for relapse or death related to disease; therefore, they could not be used in the initial risk stratification.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Expression of Ik6 and Ik8 Isoforms and Their Association with Relapse and Death in Mexican Children with Acute Lymphoblastic Leukemia

et al. 2015

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“…In an analysis of more than 250 BCR ‐ ABL1 ‐positive and ‐negative paediatric BCP ALL cases, neither intragenic IKZF1 deletions nor any expression patterns indicative of such deletions were observed (Qazi et al , ; Uckun et al , ). Furthermore, unaffected expression levels in cases with hemizygous IKZF1 deletions and low expression of IK6 in healthy controls have also been reported (Tokunaga et al , ; Volejnikova et al , ).…”

Section: Controversiesmentioning

confidence: 99%

Ikaros and leukaemia

Olsson

Johansson

2015

Br J Haematol

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SummaryThe IKZF1 gene at 7p12.2 codes for IKAROS (also termed IKZF1), an essential transcription factor in haematopoiesis involved primarily in lymphoid differentiation. Its importance is underlined by the fact that deregulation of IKAROS results in leukaemia in both mice and men. During recent years, constitutional as well as acquired genetic changes of IKZF1 have been associated with human disease. For example, certain germline single nucleotide polymorphisms in IKZF1 have been shown to increase the risk of some disorders and abnormal expression and somatic rearrangements, mutations and deletions of IKZF1 (DIKZF1) have been detected in a wide variety of human malignancies. Of immediate clinical importance is the fact that DIKZF1 occurs in 15% of paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL) and that the presence of DIKZF1 is associated with an increased risk of relapse and a poor outcome; in some studies such deletions have been shown to be an independent risk factor also when minimal residual disease data are taken into account. However, cooperative genetic changes, such as ERG deletions and CRLF2 rearrangements, may modify the prognostic impact of DIKZF1, for better or worse. This review summarizes our current knowledge of IKZF1 abnormalities in human disease, with an emphasis on BCP ALL.Keywords: IKZF1, deletion, mutation, leukaemia, prognosis.The zinc finger protein IKAROS (also termed IKZF1) is encoded by the IKZF1 gene, located in chromosome subband 7p12.2 (chr7:50,304,124-50,405,101; http://www.ensembl.org/index.html) and was first identified in 1992 as an important transcription factor for the maturation of T lymphocytes in mice (Georgopoulos et al, 1992); however, an isoform of this protein, LyF-1, had previously been reported as an essential player in the regulation of both T-and B-cell lineage specification (Lo et al, 1991).In the mid-and late-1990s, mutations of IKZF1 or abnormal expression of IKAROS were, for the first time, implicated in leukaemia and numerous subsequent studies have since addressed the pathogenetic and clinical impact of IKA-ROS and its various isoforms in human disease, revealing, for example, that germline single nucleotide polymorphisms (SNPs) in IKZF1 are associated with increased (or decreased) susceptibility to certain disorders, that a constitutional IKZF1 deletion (DIKZF1) may increase the risk of developing acute lymphoblastic leukaemia (ALL), that aberrant expression and hypermethylation of IKZF1 occurs in some solid tumours, that IKZF1 is rearranged due to translocations in a few haematological malignancies, that sequence mutations of IKZF1 (mutIKZF1) are present in both solid tumours and leukaemia, and that DIKZF1 is common in chronic myeloid leukaemia (CML) in lymphoid blast crisis and in adult and paediatric B-cell (BCP) ALL. These findings will be reviewed herein, with a focus on IKZF1 abnormalities in BCP ALL.

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“…We focused our analysis on mRNA expression comparing normal vs. ALL samples (log 2 median centered expression values for each data set) and filtered expression signals that were greater than 1.5-fold difference and P-value from two sample t-tests less than 0.001. In addition, we compiled 6 archived gene expression profiling datasets that measured expression from B-lineage ALL patients hybridized to Human Genome U133 Plus 2.0 Array, including GSE11877, n = 207; GSE13159, n = 823; GSE13351, n = 107; GSE18497, n = 82; GSE28460, n = 98; GSE7440, n = 99 (Total n = 1416), as described [28][29][30][31] .…”

Section: Gene Expression Analysesmentioning

confidence: 99%

Wilms’ tumor gene (WT1) is strongly expressed in high-risk subsets of pediatric acute lymphoblastic leukemia

Uçkun¹

2018

CDR

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Aim: The purpose of the present study was to perform a comprehensive analysis of WT1 gene expression in high-risk pediatric acute lymphoblastic leukemia (ALL). Methods: We performed a meta-analysis of WT1 gene expression for normal hematopoietic cells vs. primary leukemia cells from 801 pediatric ALL samples deposited in the Oncomine database combined with an in-depth gene expression analysis using our in-house database of gene expression profiles of primary leukemia cells from 1416 pediatric ALL cases. We also examined the expression of WT1 in primary leukemic cells from 299 T-lineage ALL patients in the Oncomine database and 189 T-lineage ALL patients in the archived datasets GSE13159, GSE13351, and GSE13159. Results: Our data provide unprecedented evidence that primary leukemia cells from patients with MLL gene rearrangements (MLL-R) express highest levels of WT1 expression within the high-risk subsets of pediatric B-lineage ALL. Notably, MLL-R + patients exhibited > 6-fold higher expression levels of the WT1 gene compared to the other B-lineage ALL subtypes combined (P < 0.0001). Our findings in 97 MLL-R + infant B-lineage ALL cases uniquely demonstrated that WT1 is expressed at 1.5-4.2-fold higher levels in MLL-R + infant leukemia cells than in normal hematopoietic cells and revealed that WT1 expression level was substantially higher in steroid-resistant infant leukemia cells when compared to non-leukemic healthy bone marrow cells. Furthermore, our study demonstrates for the first time that the WT1-regulated EWSR1 , TP53 , U2AF2 , and WTAP genes (i.e., WT1 interactome) were differentially upregulated in MLL-R + leukemia cells illustrating that the MLL-regulatory pathway is aberrantly upregulated in MLL-R + pediatric B-lineage ALL. These novel insights provide a compelling rationale for targeting WT1 in second line treatment of MLL-R + pediatric B-lineage ALL, including MLL-R + infant ALL. Furthermore, our study is the first to demonstrate that leukemia cells from 370 Ph-like patients had significantly higher WT1 expression when compared to normal hematopoietic cells. Finally, our findings demonstrate for the first time that chemotherapy-resistant primarily leukemic cells from relapsed B-lineage ALL patients exhibit higher expression levels of WT1 than primary leukemia cells from newly diagnosed B-lineage ALL patients (P = 0.001). Conclusion: Our findings indicate that the WT1 gene product may serve as a target for immunotherapy in high risk/poor prognosis subsets of newly diagnosed as well as relapsed pediatric B-lineage ALL. Our findings also significantly expand the current knowledge of WT1 expression in T-lineage ALL and provide new evidence that WT1 gene and its interactome are expressed in T-lineage ALL cells at significantly higher levels than in normal hematopoietic cells. This previously unknown differential expression profile uniquely indicates that the protein product of WT1 would be an attractive molecular target for treatment of T-lineage ALL as well.

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Constitutive Function of the Ikaros Transcription Factor in Primary Leukemia Cells from Pediatric Newly Diagnosed High-Risk and Relapsed B-precursor ALL Patients

Cited by 6 publications

References 26 publications

Expression of Ik6 and Ik8 Isoforms and Their Association with Relapse and Death in Mexican Children with Acute Lymphoblastic Leukemia

Expression of Ik6 and Ik8 Isoforms and Their Association with Relapse and Death in Mexican Children with Acute Lymphoblastic Leukemia

Ikaros and leukaemia

Wilms’ tumor gene (WT1) is strongly expressed in high-risk subsets of pediatric acute lymphoblastic leukemia

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