Identification and Characterization of Novel Fusion Genes with Potential Clinical Applications in Mexican Children with Acute Lymphoblastic Leukemia
Abstract
1. Introduction
2. Results
2.1. Clinical Features of Patients
2.2. Novel Fusion Transcripts
2.2.1. CREBBP-SRGAP2B t (16;1) (p13.3;q21.1)
2.2.2. DNAH14-IKZF1 t (1;7) (q42.12;7p12.2)
2.2.3. ETV6-SNUPN t (12;15) (p13.2;q24.2) and ETV6-NUFIP1 t (12;13) (p13.2;q14.12)
2.2.4. EP300-ZNF384 t (22;12) (q13.2;p13.31;)
3. Discussion
4. Materials and Methods
4.1. Patients and Samples
4.2. RNA-Seq Libraries and Sequencing
4.3. Reverse Transcription–Polymerase Chain Reaction (RT-PCR) for Fusion Genes
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ALL | Acute lymphoblastic leukemia |
NGS | Next-generation sequencing |
RNA-seq | RNA-sequencing |
IP | Immunophenotype |
EBV | Epstein–Barr virus |
BCP | Bicytopenia |
SS | Septic shock |
HLH | Hemophagocytic lymphohistiocytosis |
MOF | Multiple organ failure |
TC | Toxicity |
PN | Pneumonia |
CR | Complete remission central nervous system relapse |
CNS | Central nervous system |
CDS | Coding sequence |
ETS | E-twenty-six |
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Case | Age (Years) | Sex | Fusion Transcripts by NGS | Relapse | Death | Adherence | Diagnosis/Year | Initial WBC Count × 106 Cell/L | BM Blast % at Diagnosis | IP | Outcome |
---|---|---|---|---|---|---|---|---|---|---|---|
74MO | 10.8 | M | BCR-ABL minor SRGAP2B-CREBBP | Yes | SS | Yes | ALL/2013 | 15,630 | 100 | Pre-B | Progressed quickly; expired in 2 weeks |
77MO | 17.4 | M | NF | No | No | Yes | ALL/2014 | 12,570 | 98 | Pre-B | CR |
197MO | 9.4 | F | EP300-ZNF384 | No | No | Yes | ALL/2014 | 2430 | 95 | Pre-B | CR |
199MO | 3.9 | M | NF | No | SS | Yes | ALL/2014 | 440 | 100 | Pre-B | Died after remission |
63MO | 2.0 | M | TCF3-PBX1 | No | SS | Yes | ALL/2015 | 7500 | 97 | T cell | Died after remission |
123MO | 4.7 | F | NF | No | No | Yes | ALL/2015 | 42,100 | 25 | Pre-B | CR |
269MO | 4.0 | F | ETV6-RUNX1 | No | No | Yes | ALL/2015 | 9200 | 98 | Pre-B | CR |
273MO | 14.8 | M | NF | No | No | Yes | ALL/2015 | 12,460 | 96 | Pre-B | CR |
289MO | 0.6 | F | MLL-AF4, GLYR1-SLC9A8a | No | No | Yes | ALL/2015 | 371,000 | 80 | Pre-B | CR |
374MO | 4.4 | F | NF | No | No | Yes | ALL/2015 | 20,220 | 100 | Pre-B | CR |
385MO | 5.5 | M | NF | ND | ND | A | ALL/2015 | 7200 | 85 | Pre-B | ND |
405MO | 4.6 | M | NF | No | No | Yes | ALL/2015 | 2700 | 25 | Pre-B | CR |
420MO | 6.0 | F | NF | No | No | Yes | ALL/2015 | 2360 | 90 | Pre-B | CR |
545MO | 7.2 | F | WDR74-RCC1a | No | No | Yes | ALL/2015 | 8600 | 98 | Pre-B | CR |
549MO | 4.9 | M | NF | No | No | Yes | ALL/2015 | 13,300 | 98 | Pre-B | CR |
99MO | 9.8 | F | NF | No | No | Yes | ALL/2016 | 9000 | 90 | Pre-B | CR |
109MO | 4.7 | F | NF | No | No | Yes | ALL/2016 | 19,900 | 96 | Pre-B | CR |
122MO | 12.3 | M | NF | No | No | Yes | ALL/2016 | 4700 | 96 | Pre-B | CR |
179MO | 1.8 | F | DNAH14-IKZF1 | No | No | Yes | ALL/2016 | 32,780 | 100 | Pre-B | CR |
196MO | 4.1 | F | NF | No | No | Yes | ALL/2016 | 2780 | 25 | Pre-B | CR |
369MO | 2.3 | M | NF | No | No | Yes | ALL/2016 | 2710 | 100 | Pre-B | CR |
546MO | 13.0 | M | NF | No | No | Yes | ALL/2016 | 8000 | 100 | Pre-B | CR |
28MO | 10.3 | F | ETV6-SNUPN, ETV6-NUFIP1 | No | MOF TC, PN, TC. | Yes | ALL/2016 | 46,300 | 99.5 | Pre-B | Progressed quickly; poorly responded to therapy, died after 2 weeks |
73MO * | 37.3 | F | NF | ND | ND | ND | HLH/2014 | 2200 | - | NA | NA |
159MO * | 5.8 | M | NF | ND | ND | ND | EBV/2015 | 3620 | 15 | NA | NA |
165MO * | 2.2 | M | NF | ND | ND | ND | EBV/2015 | 29,740 | - | NA | NA |
83MO * | 5.8 | F | NF | ND | ND | ND | BCP/2017 | 2390 | - | NA | NA |
Fusion | Gene Symbol (Chromosome Band) | Nucleotides (hg19) | Gene Description | Sample | Gene Previously Reported as Potential Prognostic Indicator | In-Frame | Fusion Validated |
---|---|---|---|---|---|---|---|
CREBBP-SRGAP2B | SRGAP2B (1q21.1) | 144013900 | SLIT-ROBO Rho GTPase-activating protein 2B | 74MO | No reported | Yes | Yes |
CREBBP (16p13.3) | 3929832 | CREB-binding protein (CBP) | Mutations may confer to chemotherapy resistance and possibility of relapse [15] | ||||
DNAH14-IKZF1 | DNAH14 (1q41.12) | 225333860, 225333863, 225347499, 225354984, 225374260, 225346497 | Dynein Axonemal Heavy Chain 14 | 179MO | No reported | Yes | Yes |
IKZF1 (7p12.2) | 50444490, 50367352, 50435762, 50444490, 50448363, 50444230 | IKAROS Family Zinc Finger 1 | Deletions and mutation were related to adverse prognosis, treatment failure, and risk of relapse [16,17,18] | ||||
ETV6-SNUPN | ETV6 (12p13.2) | 11905512 | ETS family transcription factor, Variant 6 | 28MO | In fusion with RUNX1, the most common genetic aberration in pediatric ALL and is related to favorable prognosis [19] | Yes | Yes |
SNUPN (15q24.2) | 75913396 | Snurportin 1 | No reported | ||||
ETV6-NUFIP1 | ETV6 (12p13.2) | 11803093 | ETS family transcription factor, Variant 6 | 28MO | Yes | Yes | |
NUFIP1 (13q14.12) | 45540070 | Nuclear Fragile X Mental Retardation Protein Interacting Protein 1 | No reported | ||||
EP300-ZNF384 | ZNF384 (12p13.31) | 6788687 | Zinc finger protein 384 | 197MO | EP300-ZNF384 fusion is associated with a B-cell precursor ALL in childhood (3–4%) with better favorable response to chemotherapy than patients with MLL translocations [14] | Yes | Yes |
EP300 (22q13.2) | 41527639 | E1A binding protein p300 |
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Mata-Rocha, M.; Rangel-López, A.; Jiménez-Hernández, E.; Morales-Castillo, B.A.; González-Torres, C.; Gaytan-Cervantes, J.; Álvarez-Olmos, E.; Núñez-Enríquez, J.C.; Fajardo-Gutiérrez, A.; Martín-Trejo, J.A.; et al. Identification and Characterization of Novel Fusion Genes with Potential Clinical Applications in Mexican Children with Acute Lymphoblastic Leukemia. Int. J. Mol. Sci. 2019, 20, 2394. https://doi.org/10.3390/ijms20102394
Mata-Rocha M, Rangel-López A, Jiménez-Hernández E, Morales-Castillo BA, González-Torres C, Gaytan-Cervantes J, Álvarez-Olmos E, Núñez-Enríquez JC, Fajardo-Gutiérrez A, Martín-Trejo JA, et al. Identification and Characterization of Novel Fusion Genes with Potential Clinical Applications in Mexican Children with Acute Lymphoblastic Leukemia. International Journal of Molecular Sciences. 2019; 20(10):2394. https://doi.org/10.3390/ijms20102394
Chicago/Turabian StyleMata-Rocha, Minerva, Angelica Rangel-López, Elva Jiménez-Hernández, Blanca Angélica Morales-Castillo, Carolina González-Torres, Javier Gaytan-Cervantes, Enrique Álvarez-Olmos, Juan Carlos Núñez-Enríquez, Arturo Fajardo-Gutiérrez, Jorge Alfonso Martín-Trejo, and et al. 2019. "Identification and Characterization of Novel Fusion Genes with Potential Clinical Applications in Mexican Children with Acute Lymphoblastic Leukemia" International Journal of Molecular Sciences 20, no. 10: 2394. https://doi.org/10.3390/ijms20102394
APA StyleMata-Rocha, M., Rangel-López, A., Jiménez-Hernández, E., Morales-Castillo, B. A., González-Torres, C., Gaytan-Cervantes, J., Álvarez-Olmos, E., Núñez-Enríquez, J. C., Fajardo-Gutiérrez, A., Martín-Trejo, J. A., Solís-Labastida, K. A., Medina-Sansón, A., Flores-Lujano, J., Sepúlveda-Robles, O. A., Peñaloza-González, J. G., Espinoza-Hernández, L. E., Núñez-Villegas, N. N., Espinosa-Elizondo, R. M., Cortés-Herrera, B., ... Mejía-Aranguré, J. M. (2019). Identification and Characterization of Novel Fusion Genes with Potential Clinical Applications in Mexican Children with Acute Lymphoblastic Leukemia. International Journal of Molecular Sciences, 20(10), 2394. https://doi.org/10.3390/ijms20102394