IKZF1 Deletions with COBL Breakpoints Are Not Driven by RAG-Mediated Recombination Events in Acute Lymphoblastic Leukemia

Abstract

IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.

Integrated Analysis Reveals ENDOU as a Biomarker in Head and Neck Squamous Cell Carcinoma Progression

“…Fibroblast Activation Protein Alpha (FAP) was proven to serve as a marker in metastatic prostate cancer (53), pancreatic cancer (54) and ovarian cancer (55). Cordon-Bleu WH2 Repeat Protein (COBL) has been reported to play an important role in the reorganization of the actin cytoskeleton (25)(26)(27), and as a hotspot for IKZF1 deletions (28) in acute lymphoblastic leukemia. Dual Specificity Phosphatase 5 (DUSP5) is tumor suppressor in ovarian cancer (56).…”

“…Cordon-Bleu WH2 Repeat Protein (COBL) contains WH2 domains (WASP, Wiskott-Aldrich syndrome protein, homology domain-2) and has been reported to play an important role in the reorganization of the actin cytoskeleton (25)(26)(27). In acute lymphoblastic leukemia, COBL is a hotspot for IKZF1 deletions (28), and we will study the function of COBL in HNSCC in the future. ENDOU, also known as PP11 (Placental Protein 11), encodes uridylate-specific endoribonuclease expressed in the placenta.…”

IKZF1 deletions in pediatric acute lymphoblastic leukemia: still a poor prognostic marker?

“…In addition, an increasing number of cases with fusion transcripts involving IKZF1 have been described (Figure 1). [17][18][19][20][21][22][23][24][25][26] Besides the somatic alterations described earlier in this section, frequent intronic germline variants in IKZF1 (rs11978267 and rs4132601) have been identified in genome-wide association studies and consistently described to modestly modulate the risk of pediatric BCP ALL (Figure 1). 27,28 Of major importance, Churchman et al recently characterized IKZF1 as a leukemia predisposition gene by reporting mostly adverse germline IKZF1 variation in familial pediatric ALL and 43 of 4963 (0.9%) unselected BCP ALL patients 29 (Figure 1).…”

“…9,48 IKZF1 sequence mutations were mainly analyzed by Sanger sequencing and targeted or nontargeted next-generation sequencing strategies whereas the majority of fusion genes have been identified in transcriptomic studies. 10,[13][14][15][16][17][18][19][20][21][22][23][24][25][26]29 The different qualities and sensitivities of these techniques need to be considered when comparing frequency and type of IKZF1 aberrations in the literature.…”

Prognostic significance of copy number variation in B-cell acute lymphoblastic leukemia

“…However, some research of gene prognostic value is inconsistent, which could be because of difference in enrolled patients and treatment regimen. Undoubtedly, CNVs guided the risk of relapsing and survival outcome of both pediatric and adult B-ALL ( 84 ). Intensive chemotherapy combined with allo-HSCT is expected to overcome the adverse impact of CNVs.…”