Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011

Abstract

, Castor, A., Behrendtz, M., Biloglav, A., Forestier, E., Paulsson, K., & Johansson, B. (2014). Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011. Leukemia, 28(2), 302-310. DOI: 10.1038DOI: 10. /leu.2013 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal and TBL1XR1 were significantly more common in B-cell precursor ALL patients who relapsed compared with those remaining in complete remission. In univariate analyses, age (≥10 years), WBC counts (>100 x 10 9 /l), t(9;22)(q34;q11), MLL rearrangements, nearhaploidy, and deletions of ATP10A, IKZF1, SPRED1, and the pseudoautosomal 1 regions on Xp/Yp were significantly associated with decreased 10-year event-free survival, with IKZF1 abnormalities being an independent risk factor in multivariate analysis irrespective of risk group. High age and deletions of IKZF1 and SPRED1 were also associated with poor overall survival. Thus, analyses of these genes provide clinically important information.

Characterization of leukemias with ETV6-ABL1 fusion

“…CDKN2A and CDKN2B as well as BTLA and CD200 genes were co-deleted in all cases, thus the pairs are merged into one column. Deletion of ATP10A was recently shown to be a recurrent aberration in BCP-ALL, associated with decreased 10-year event-free survival 56 . Gray indicates loss, black indicates a gain, deleted exons within IKZF1, ABL1 and ETV6 genes are indicated by numerals (for IKZF1 white numerals depict losses resulting in a dominant negative IKZF1 isoform or complete loss of IKZF1 expression, black numerals depict haploinsufficiency with the potential exception of combined 2-3/4-7 loss which can affect either a single allele or both gene alleles and thus can result in either haploinsufficiency or complete loss).…”

Novel gene targets detected by genomic profiling in a consecutive series of 126 adults with acute lymphoblastic leukemia

“…4,7,8 Whether the pattern of microdeletions, as ascertained by single nucleotide polymorphism (SNP) array analysis, also differs between childhood and adult BCP ALL is less well clarified because most analyses of ALL have been performed on pediatric cases. 9,10 In fact, SNP array findings in adult ALL have so far been reported in only three larger series, [11][12][13] one of which focused solely on IKZF1 deletions. 13 The two other studies 11,12 identified similar gene deletions to those found in pediatric cases, namely losses of CDKN2A, PAX5, IKZF1, ETV6, RB1, EBF1 and LEF1.…”

Loss of TBL1XR1 Disrupts Glucocorticoid Receptor Recruitment to Chromatin and Results in Glucocorticoid Resistance in a B-Lymphoblastic Leukemia Model

“…Evidence for the role of these genes in the development of relapse was described by Mullighan et al (7) in a study showing that deletions in TBL1XR1, BTG1, and NR3C1 are selected for during the clonal evolution of ALL that results in relapsed disease. TBL1XR1 deletions are poor prognostic markers (9) and are enriched during the evolution of relapsed disease (7), indicating a role in GC resistance and eventual relapse.…”

“…TBL1XR1 deletions are enriched at relapse compared with diagnosis (6 -8), and importantly TBL1XR1 deletions at diagnosis occur more frequently in patients that ultimately relapse (9). TBL1XR1 is a member of the nuclear receptor corepressor (NCoR) complex and is responsible for the degradation of NCoR (10,11).…”