CD22 Exon 12 Deletion as an Independent Predictor of Poor Treatment Outcomes in B-ALL
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Comparative Analysis of the Expression Levels of CD22 Exons 11−14 in Primary Leukemia Cells from Newly Diagnosed Pediatric Patients with B-All and Normal Hematopoietic Cells from Non-Leukemic Controls Using a Human Genome Expression Microarray Platform for Transcriptome Profiling
2.2. Detection of CD22ΔE12 mRNA in B-ALL Leukemia Samples via Real-Time Quantitative RT-PCR
2.3. Data Normalization for Exon-Level CD22 Gene Expression Data Derived from Primary B-ALL Cells
2.4. Hierarchical Clustering Analysis to Identify CD22E12low B-ALL Patients
2.5. Normalization of Gene Level RNAseq Data Derived from Primary B-ALL Cells
2.6. Gene Set Enrichment Analysis (GSEA) for Evaluation of Reactome Pathways in B-ALL Patients with Low CD22E12 Expression
2.7. Analysis of Treatment Outcomes according to RNAseq-Based CD22E12 mRNA Expression Levels
2.8. Multivariate and Univariate Cox Regression Models to Test for the Independent Effect of CD22E12low Status
3. Results
3.1. Interpatient Heterogeneity in Microarray-Based CD22E12 and qRT-PCR-Based CD22ΔE12 mRNA Expression Levels among Newly Diagnosed B-ALL Patients
3.2. Interpatient Heterogeneity in Selective Reduction of RNAseq-Based CD22E12 Expression Levels among B-ALL Patients
3.3. Presenting Features of CD22E12low B-ALL Patients
3.4. Gene Set Enrichment Analysis of Reactome Pathways in CD22E12low B-ALL Patients
3.5. Clinical Prognostic Significance of the Interpatient Heterogeneity in Selective Reduction of RNAseq-Based CD22 Exon 12 Expression Levels among B-ALL Patients
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variable | CD22E12low (N = 21) | All Others (N = 120) | p-Value | |||
---|---|---|---|---|---|---|
Mean/Median(Range) orN (% Evaluable) | Mean/Median(Range) or N (% Evaluable) | Mann-Whitney U Test or Fisher’s Exact | ||||
Age (yrs) | ||||||
Mean ± SEM/Median (Range) | 8.2 ± 1.2 | 7.6 (1.4–18.1) | 7.9 ± 0.5 | 6.4 (1.2–30) | 0.8 | |
WBC (×109/L) | ||||||
Mean ± SEM/Median (Range) | 45.5 ± 13.1 | 15.9 (1.3–214.5) | 76.8 ± 12 | 33 (1.1–1149) | 0.2 | |
MRD at Day 29 | ||||||
Mean ± SEM/Median (Range) | 0.07 ± 0.03 | 0 (0–0.57) | 0.9 ± 0.4 | 0 (0–26) | 0.4 | |
MRD at End of Consolidation | ||||||
Mean ± SEM/Median (Range) | 0 ± 0 (N = 3) | 0 (0–0) | 1.6 ± 1.4 (N = 23) | 0 (0–31.5) | 0.3 | |
Age category | ||||||
Adult (≥18 yrs) | 1/21 | (4.8%) | 4/120 | (3.3%) | 0.6 | |
CNS Status at Diagnosis | ||||||
CNS 2 + CNS 3 Induction Failure | 5/21 0/21 | (23.8%) (0%) | 23/120 2/119 | (19.2%) (1.7%) | 0.6 1.0 | |
NCI Risk | ||||||
High Risk | 11/21 | (52.4%) | 79/120 | (65.8%) | 0.3 | |
Age risk | ||||||
Poor (Age <2 yrs or ≥10 years) | 11/21 | (52.4%) | 53/120 | (44.2%) | 0.6 | |
WBC category | ||||||
≥20 × 109/L MRD at Day 8 MRD > 0 | 10/21 7/7 | (47.6%) (100%) | 73/120 33/33 | (60.8%) (100%) | 0.3 1.0 | |
MRD at Day 29 | ||||||
MRD > 0 MRD at End of Consolidation MRD > 0 | 9/21 0/3 | (42.9%) (0%) | 64/120 8/23 | (53.3%) (34.8%) | 0.5 0.5 | |
Cytogenetics (N = 106) | ||||||
Pseudodiploid | 5/12 | (41.7%) | 38/94 | (40.4%) | 1.0 | |
Pseudodiploid + Hypodiploid or Hyperdiploid with SCA | 7/12 | (58.3%) | 71/94 | (75.5%) | 0.3 | |
Molecular Markers/FISH (N = 132) | ||||||
BCR-ABL1 | 0/20 | (0%) | 5/112 | (4.5%) | 1.0 | |
MLL/KMT2A rearranged | 0/20 | (0%) | 4/112 | (3.6%) | 1.0 | |
TCF3-PBX1 | 3/20 | (15%) | 11/112 | (9.8%) | 0.4 | |
Hyperdiploid with Trisomy of chromosomes 4 and 10 | 0/20 | (0%) | 10/112 | (8.9%) | 0.4 | |
ETV6-RUNX1 | 0/20 | (0%) | 11/112 | (9.8%) | 0.2 | |
ETV6-RUNX1 + Trisomy of chromosomes 4 and 10 | 0/20 | (0%) | 21/112 | (18.8%) | 0.04 |
Reactome Pathway | Enrichment Score in CD22E12low B-ALL | Enrichment Score in CD22ΔE12-Tg Mice | ||
---|---|---|---|---|
NES | p-Value | NES | p-Value | |
Reactomes Involved in Transcription | ||||
mRNA 3’-end processing | 2.4 | 2.8 × 10−5 | 2.4 | 1.3 × 10−5 |
RNA polymerase II transcription termination | 2.3 | 2.8 × 10−5 | 2.5 | 1.3 × 10−5 |
Transport of mature mRNA derived from an intronless transcript | 2.1 | 2.7 × 10−5 | 2.4 | 1.4 × 10−5 |
RNA polymerase II pretranscription events | 1.8 | 4.7 × 10−4 | 2.6 | 1.2 × 10−5 |
RNA polymerase II transcription elongation | 1.7 | 1.6 × 10−3 | 2.4 | 1.3 × 10−5 |
Transcriptional regulation by small RNAs | 1.5 | 9.9 × 10−3 | 2.4 | 1.3 × 10−5 |
Positive epigenetic regulation of rRNA expression | 1.5 | 1.9 × 10−2 | 2.0 | 1.3 × 10−5 |
Reactomes Involved in mRNA Processing | ||||
Regulation of mRNA stability by proteins that bind AU-rich elements | 1.8 | 2.4 × 0−4 | 2.5 | 1.2 × 10−5 |
mRNA splicing—minor pathway | 1.6 | 1.3 × 10−2 | 2.3 | 1.3 × 10−5 |
tRNA processing in the nucleus | 1.5 | 2.3 × 10−2 | 2.5 | 1.3 × 10−5 |
Metabolism of non-coding RNA | 1.5 | 3.0 × 10−2 | 2.6 | 1.3 × 10−5 |
Reactomes Involved in mRNA Transport | ||||
Transport of mature transcript to cytoplasm | 2.6 | 3.0 × 10−5 | 2.6 | 1.2 × 10−5 |
Transport of mature mRNA derived from an intron-containing transcript | 2.5 | 2.9 × 10−5 | 2.6 | 1.3 × 10−5 |
Transport of mature mRNAs’ intronless transcripts | 2.2 | 2.7 × 10−5 | 2.4 | 1.3 × 10−5 |
Reactomes Involved in Translation | ||||
Formation of a pool of free 40S subunits | 3.0 | 3.1 × 10−5 | 2.8 | 1.2 × 10−5 |
Eukaryotic translation elongation | 3.0 | 3.0 × 10−5 | 2.8 | 1.2 × 10−5 |
Peptide chain elongation | 2.9 | 3.0 × 10−5 | 2.7 | 1.2 × 10−5 |
Eukaryotic translation termination | 2.6 | 3.0 × 10−5 | 2.7 | 1.2 × 10−5 |
Ribosomal scanning and start codon recognition | 2.6 | 2.8 × 10−5 | 2.6 | 1.3 × 10−5 |
Translation initiation complex formation | 2.6 | 2.8 × 10−5 | 2.6 | 1.3 × 10−5 |
Activation of the mRNA upon binding of the cap-binding complex and eIFs and subsequent binding to 43S | 2.4 | 2.8 × 10−5 | 2.6 | 1.3 × 10−5 |
Formation of the ternary complex and, subsequently, the 43S complex | 2.4 | 2.7 × 10−5 | 2.5 | 1.3 × 10−5 |
Reactomes Involved in Post-Translational Protein Modification | ||||
SUMOylation of RNA binding proteins | 2.2 | 2.7 × 10−5 | 2.4 | 1.3 × 10−5 |
Synthesis of active ubiquitin: roles of E1/E2 enzymes | 2.2 | 2.5 × 10−5 | 2.0 | 1.8 × 10−4 |
SUMOylation of SUMOylation proteins | 2.1 | 7.7 × 10−5 | 2.3 | 1.4 × 10−5 |
SUMOylation of DNA replication proteins | 2.0 | 1.1 × 10−4 | 2.4 | 1.3 × 10−5 |
SUMOylation of ubiquitinylation proteins | 2.0 | 2.9 × 10−4 | 2.3 | 1.4 × 10−5 |
Protein ubiquitination | 2.0 | 8.6 × 10−5 | 2.3 | 1.3 × 10−5 |
SUMOylation of transcription cofactors | 1.9 | 3.2 × 10−4 | 1.9 | 7.9 × 10−5 |
SUMOylation of chromatin organization proteins | 1.8 | 1.1 × 10−3 | 2.3 | 1.3 × 10−5 |
SUMOylation of DNA damage response and repair proteins | 1.6 | 7.1 × 10−3 | 2.4 | 1.2 × 10−5 |
Reactomes Involved in Signal Transduction | ||||
RAF activation | 2.2 | 2.6 × 10−5 | 1.7 | 8.7 × 10−3 |
MAP kinase activation | 1.9 | 2.5 × 10−4 | 1.5 | 1.5 × 10−2 |
RHOBTB2 GTPase cycle | 1.9 | 2.1 × 10−3 | 1.8 | 2.7 × 10−3 |
Regulation of RAS by GAPs | 1.9 | 2.6 × 10−4 | 2.0 | 1.2 × 10−5 |
MAPK6/MAPK4 signaling | 1.8 | 4.5 × 10−4 | 2.1 | 1.2 × 10−5 |
Reactomes Involved in Cell Cycle Pathway | ||||
Postmitotic nuclear pore complex (NPC) reformation | 1.9 | 1.5 × 10−3 | 2.1 | 4.2 × 10−5 |
Nuclear envelope (NE) reassembly | 1.8 | 9.7 × 10−4 | 2.2 | 1.2 × 10−5 |
Mitotic telophase/cytokinesis | 1.8 | 1.2 × 10−2 | 1.9 | 1.3 × 10−5 |
Regulation of apoptosis | 1.7 | 3.8 × 10−3 | 2.2 | 1.3 × 10−5 |
Establishment of sister chromatid cohesion | 1.7 | 2.4 × 10−2 | 1.9 | 1.3 × 10−3 |
Nuclear pore complex (NPC) disassembly | 1.7 | 7.9 × 10−3 | 2.3 | 1.4 × 10−5 |
Nuclear envelope breakdown | 1.6 | 1.3 × 10−2 | 2.3 | 1.3 × 10−5 |
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal | 1.5 | 1.3 × 10−2 | 2.7 | 1.2 × 10−5 |
Amplification of signal from the kinetochores | 1.5 | 1.3 × 10−2 | 2.7 | 1.2 × 10−5 |
APC/C-mediated degradation of cell cycle proteins | 1.5 | 1.6 × 10−2 | 2.4 | 1.2 × 10−5 |
Regulation of mitotic cell cycle | 1.5 | 1.6 × 10−2 | 2.4 | 1.2 × 10−5 |
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Qazi, S.; Uckun, F.M. CD22 Exon 12 Deletion as an Independent Predictor of Poor Treatment Outcomes in B-ALL. Cancers 2023, 15, 1599. https://doi.org/10.3390/cancers15051599
Qazi S, Uckun FM. CD22 Exon 12 Deletion as an Independent Predictor of Poor Treatment Outcomes in B-ALL. Cancers. 2023; 15(5):1599. https://doi.org/10.3390/cancers15051599
Chicago/Turabian StyleQazi, Sanjive, and Fatih M. Uckun. 2023. "CD22 Exon 12 Deletion as an Independent Predictor of Poor Treatment Outcomes in B-ALL" Cancers 15, no. 5: 1599. https://doi.org/10.3390/cancers15051599