Comprehensive Overview of Gene Rearrangements in Childhood T-Cell Acute Lymphoblastic Leukaemia
Abstract
:1. Introduction
2. Genetic Profile of T-ALL
2.1. Transcription Factor
2.2. Signalling Pathway Regulators
2.2.1. NOTCH1 Pathway
2.2.2. PI3-AKT-mTOR Pathway
2.2.3. JAK-STAT Pathway
2.2.4. RAS Pathway
2.3. Cell Cycle Regulators
2.4. Kinase Signalling
2.5. T-ALL Rearrangements
2.6. Epigenetic Regulators
2.7. Tumour Suppressors
2.8. Translation and RNA Stability
3. Genetic Aberrations Involved in Relapse
4. Chromothripsis
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AKT1 | the serine-threonine protein kinase |
ALL | acute lymphoblastic leukemia |
BCP-ALL | B-cell precursor acute lymphoblastic leukemia |
BSAP | B-cell-specific protein activator factor |
CIR | cumulative incidence of relapse |
CNAs | copy number alterations |
DFR | disease free of recurrence |
DIC | disseminated intravascular coagulation |
DR | Downregulation |
EGIL | The European Group for the Immunologic Classification |
ESF | event-free survival |
ETP-ALL | Early T-cell precursor ALL |
GSI | γ-secretase inhibitors |
HD | heterodimerization domain |
JAK 1 | janus kinase 1 |
LBL | acute lymphoblastic lymphoma |
LDH | lactate dehydrogenase |
MRD | minimal residual disease |
NGS | new generation sequencing |
OE | Overexpression |
OS | overall survival |
PDGFRb | platelet dderived growth factor b |
PEST | (-Pro-Gln-Ser-Thr-) domain. |
PIP2 | phosphatidylinositol (4,5) P2 |
PIP3 | phosphatidylinositol (3,4,5) P3 |
PRC | polycomb group complex |
RFS | relapse-free survival |
SNV | single nucleotide variants |
STAT5B | signal transducer and activator of transcription 5B |
T-ALL | T-cell acute lymphoblastic leukemia |
TCR | T cell antigen receptor |
TKI | tyrosine kinase inhibitor |
WBC | white blood cell |
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Gene | Locus | Alterations | Partners gene | Incidence | Relevance | References |
---|---|---|---|---|---|---|
TAL1 (SCL, TCL5) | 1p32 | Overexpression with coexisting LMO1/2 | STIL (1p33) | 30–37.5% | Adverse, potential MRD marker | [29,33] |
deletions | - | 7.7–25% | [65,66,67] | |||
TLX3 (HOX11L2) | 5q35 | Overexpression | BCL11B (14q32) | 20–24% | Adverse | [29] |
TLX1 (HOX11) | 10q24 | TCRD (14q11) | 3–8% | Favorable | [29,34] | |
Expression level | TCRB (7q35) | OE 1 19.7%, LE 2 28.9% | N/A 3 | |||
NKX2-1 NKX2-2 | 14q13 20p11 | Overexpression | - | 5.9% | Unidentified | [29] |
LMO1 (TTG1) | 11p15 | Translocations | TRB (7q34) TRA (14q11.2) TRD (14q11) | <1% | Unidentified | [41] |
LMO2 (TTG2) | 11p13 | Translocations | TRA (14q11.2) FOXJ3 (1p34) | 7.7% 5% | Unidentified | [41] |
Deletions | del(1)(p12p13) | |||||
MEF2C | 5q14.3 | Overexpression | CLINT1 (5q33.3) | 2.5% | Adverse, reduce response to steroids | [13,29] |
BCL11B (CTIP2) | 14q32.2 | Mutations | - | 2–9% | Unidentified | [47,48] |
KMT2A (MLL) | 11q23 | Rearrangements | Various partners gene | 4–12% | Adverse | [35,36,37,38,39,40] |
MYB | 6q23 | Rearrangements | TCRB (7q34) SLC12A9 (7q22) PLAGL1 (6q24) BDP1 (95q13) CHMP1A (16q24) | 4.17% | Unidentified | [41] |
Mutations | - | 4.92% | [41] | |||
Amplifications | - | 12.5–12.94% | [41,42] | |||
MYC | 8q24 | Translocations | TRA (14q11) | 6.1% | Unidentified | [44] |
RUNX1 (AML1, CBFA2, PEBP2AB) | 21q22.12 | Mutations | - | 12.7%; | Adverse | [17] |
ETV6 (TEL) | 12q13.2 | Deletions | - | 5.6–6% | Unidentified | [49,50] |
Translocations | ABL1 (9q34), CTNNB1 (3p22.1) | <1% | [41] | |||
GATA3 | 10p14 | Inactivating mutations | - | 9% of paediatric patients with ETP-ALL | Adverse | [52,53] |
LEF1 (TCF10) | 4q25 | Deletions | - | 7–24.5%, | Divided | [41,43,55,56,57] |
WT1 | 11p13 | Mutations | - | 9.1–13.2% | N/A | [41,58] |
NF1 | 17q11.2 | Deletions | - | 7.4% | adverse, resistance to treatment induction | [43] |
IKZF1 (LYF1) | 7p12.2 | Loss of its function | - | 7.4% | Adverse, especially in B cell precursor (BCP)-ALL | [41,43,49,63] |
Deletions | 2.8% | |||||
Mutations | 2% | |||||
PAX5 (BSAP) | 9p13.2 | Loss of its function, deletions and mutations | - | 11–14% | Unidentified | [42,43,49] |
IKZF2 | 2q34 | loss of its function, deletions and mutations | - | 3.4% | Unidentified | [63] |
Gene | Locus | Alterations | Incidence | Relevance | References |
---|---|---|---|---|---|
NOTCH1 | 9q34.3 | Activating mutations | 51.1–74.6% | Favorable, targeted therapy—γ-secretase inhibitors (GSI) | [41,68] |
t(7;9)(q34:q34.3) | <1% | ||||
FBXW7 | 4q31.3 | Inactivating mutations | 22.4–23.9% | Unidentified | [41,68] |
PIK3CD (PI3K-DELTA) | 1p36.22 | Deletions | 4.65% | Unidentified, targeted therapy—PI3K inhibitors | [42] |
Mutations | 1.9% | [41] | |||
AKT | 14q32.33 | Deletions | 6.98% | Adverse, resistance to steroids, targeted therapy—AKT inhibitors | [42,56] |
PTEN | 10q23.31 | Mutations | 9–14% | Adverse, reduced response to treatment | [41,42,72,73,74] |
Deletions | 8.7–16% | ||||
DNM2 | 19p13.2 | Inactivating mutations | 11% | Unidentified | [41] |
IL7R | 5p13 | Activating mutations | 6.8% | Unidentified | [41] |
JAK3 | 19p13.11 | Activating mutations | 7.6% | Unidentified | [41] |
PTPN2 | 18p11.21 | Deletions | 6% | Favorable, good steroid response | [31] |
CRLF2 | Xp22.3 and Yp11.3 | Overexpression | 14.6% | Adverse, resistance to steroids | [75] |
N-RAS | 1p13.2 | Activating mutations | 6.2–10.8% | Adverse, resistance to steroids, associated with relapse | [9,11,17,41,57,77,78] |
K-RAS | 12p12.1 | Activating mutations | 2.1–11.4% | Adverse, resistance to steroids, associated with relapse | [9,11,17,57,77,78] |
Gene | Locus | Alterations | Incidence | Relevance | References |
---|---|---|---|---|---|
CDKN2A (p16(INK4A)) | 9p21.3 | Deletions, mutations, promoter hypermethylation | 66% | Divided | [11,17,79,80] |
CDKN2B (p15(INK4B)) | 9p21.3 | Deletions, mutations, promoter hypermethylation | 55% | Divided | [11,17,79,80] |
CDKN1B (p27(KIP1)) | 12p13.1 | Deletions; cooccurrence with MEF2C dysregulation | 12% | Adverse, reduced response to steroids | [13] |
CCND2 | 12p13.32 | Overexpression | 3.4% | Unidentified | [83] |
Gene | Locus | Alterations | Partner Genes | Incidence | Relevance | References |
---|---|---|---|---|---|---|
PDGFRb | 5q32 | Rearrangements | EBF1 (5q33.3), SATB1 (3p24.3), AGGF1 (5q13.3) DOCK2 (5q35.1) | single cases | Adverse, tyrosine kinase inhibitor (TKI) treatment | [85,86] |
ABL1 | 9q34.12 | Rearrangements, amplifications | NUP214 (9q34.13) | 5–6% | Adverse, TKI treatment | [42,88,89] |
BCR (22q11.23), ETV6 (12p13.2), ZBTB16 (11q23.2), EML1 (14q32.2) | <1% | |||||
FLT3 (STK1) | 13q12.2 | Mutations | - | 3.0–3.8% | N/A | [47,77] |
Fusion | Locus | Alterations | Incidence | Relevance | References |
---|---|---|---|---|---|
SIL-TAL1 | 1p32; 1p33 | Rearrangements | 16–38.5% | Adverse | [8,90,91,92] |
PICALM-MLLT10 (CALM-AF10) | 11q14.2; 10p12.31 | Rearrangements, t(10;11)(p12-13;q14-21) | 7% | Adverse/unidentified | [93,94] |
SET-NUP214 | 9q34.11; 9q34.13 | Rearrangements | 15% | Unidentified; potential minimal residual disease (MRD) marker | [96,97] |
Gene | Locus | Alterations | Incidence | Relevance | References |
---|---|---|---|---|---|
EZH2 (KMT6A, ENX1) | 7q36.1 | Inactivating mutations and promoter hypermethylation | 3.3% (adult) | Adverse, less opportunity to obtain disease-free survival (DFS) | [100] |
EED | 11q14.2 | Inactivating mutations | |||
SUZ12 (JJAZ1) | 17q11.2 | Inactivating mutations | 0–7.4% | Adverse | [43,57] |
Gene | Locus | Alterations | Incidence | Relevance | References |
---|---|---|---|---|---|
PHF6 | Xq26.2 | Mutations | 5.4–26.7% | Adverse, resistance to steroids | [41,42,91,101,102,103] |
Deletions | 2.5% | [91] | |||
TP53 | 17p13.1 | Mutations and promoter hypermethylation | 5% | Adverse, reduced response to treatment and shorter OS | [56] |
RB1 | 13q14.2 | Mutations | 9.5% | - | [41] |
Deletions | 5.6–8.3% | [49,64] |
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Mroczek, A.; Zawitkowska, J.; Kowalczyk, J.; Lejman, M. Comprehensive Overview of Gene Rearrangements in Childhood T-Cell Acute Lymphoblastic Leukaemia. Int. J. Mol. Sci. 2021, 22, 808. https://doi.org/10.3390/ijms22020808
Mroczek A, Zawitkowska J, Kowalczyk J, Lejman M. Comprehensive Overview of Gene Rearrangements in Childhood T-Cell Acute Lymphoblastic Leukaemia. International Journal of Molecular Sciences. 2021; 22(2):808. https://doi.org/10.3390/ijms22020808
Chicago/Turabian StyleMroczek, Anna, Joanna Zawitkowska, Jerzy Kowalczyk, and Monika Lejman. 2021. "Comprehensive Overview of Gene Rearrangements in Childhood T-Cell Acute Lymphoblastic Leukaemia" International Journal of Molecular Sciences 22, no. 2: 808. https://doi.org/10.3390/ijms22020808