Epigenetic Control of Infant B Cell Precursor Acute Lymphoblastic Leukemia
Abstract
:1. Introduction
2. Epigenetic Alterations That Affect Gene Expression in BCP-ALL
2.1. Role of Epigenetic Modifications in Cancer
2.2. Histone Methylation Pattern Alterations
2.2.1. Histone 3 Lysine 4 (H3K4) and Lysine 79 (H3K79) Methylation
2.2.2. Histone 3 Lysine 27 (H3K27) Methylation
2.2.3. Histone 3 Lysine 9 (H3K9) and Lysine 36 (H3K36) Methylation
2.2.4. Other Histone Alterations Affecting Methylation Patterns
2.3. DNA Methylation
- TCF3-PBX1: Given the low incidence of this subtype, DNA methylation levels in these patients have not been widely studied. However, the signature seems mostly to be hypomethylated [104].
- BCR-ABL1 ALL: The Philadelphia chromosome is an indicator of poor prognosis in ALL, and targeted therapies with imatinib or dasatinib are used to treat these patients [104]. Remarkably, DNA methylation plays a secondary role in these patients. In fact, only 271 subtype-specific differentially methylated CpG sites in 36 genes were detected in the BCR-ABL1 ALL subtype, while other subtypes harbored around 2000 differentially methylated CpG sites [100]. The effect of DNA methylation in BCR-ABL1 ALL is probably indirect, and the aberrant alterations in gene expression are far from being a direct consequence of DNA methylation pattern modifications [94].
- Intrachromosomal amplification of chromosome 21 (iAMP21): This subtype has not been widely studied because of its low incidence. However, the signatures of iAMP21 and HeH cases overlap to some extent [100].
2.4. Histone acetylation Alterations
2.5. Histone Ubiquitination Alterations
3. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Histone Mark | Regulators | Effect on Chromatin Conformation | Alteration of Gene Expression and Biological Processes | References |
---|---|---|---|---|
Histone methylation | ||||
H3K4me3 | KMT2A chromosomal rearrangements Cofactors: WDR5, RbBP5, ASHL2, DPY-30, Menin PAF1 and E2/E3 complexes | Transcriptionally active chromatin, that can turn into repressive state, depending on other marks | Regulation of proper B lymphocyte development Oncogenic drivers, such as FLT3 It can activate IKZF1 gene | [24,25,26,27,28,29,30,31,32,33,34] |
H3K79me3 | Members of super elongation complex (SEC), such as AF4, AF9 or ENL DOT1L, NSD1, CARM1 PAF1 and E2/E3 complexes | Increased chromatin accessibility, allows binding of transcription factors to promoter regions | Negative outcome markers: CPEB2, MBNL1, MCL1, RUNX1, RUNX2, ZEB2 | [29,35,36,37,38,39,40,41] |
H3K9me3 | IKZF1, SIRT1 | Repressive chromatin state | Repression of genes involved in cell cycle progression (CDC2, CDC7) | [40,42,43,44] |
H3K36me2/3 | Catalyzed by NSD2 | Present at bodies of transcriptionally active genes, impairing aberrant transcriptional initiation | This mark impairs aberrant leukemogenic activity. NSD2 mutation triggers cell proliferation | [45,46,47,48,49] |
H3K27me3 | EZH2, IKZF1, NuRD repressive complex (including HDAC1, HDAC2 and MI-2) | Close chromatin conformation | Tumor suppressor function, preventing cell cycle progression | [43,44,45,50,51] |
H4R3sme2 | PRMT5 | Closed chromatin conformation at promoter regions | Repression of genes involved in proper B cell differentiation and apoptosis (like CLC and CTSB) | [52,53,54] |
Histone acetylation | ||||
H3K27ac | EZH2 loss-of-function, EP300, KMT2A-AF4 fusion protein | Increased chromatin accessibility in enhancer regions, recruiting CTCF, GR and PU.1 factors | Induction of BIM target gene, marker of glucocorticoid sensitivity. Activation of BCL2 antiapoptotic gene and oncogene FLT3 | [33,45,55,56] |
H3K9ac and H4K16ac | KMT2A-AF4 fusion protein, in association with MOF | Active marks on promoter regions, allowed by hypomethylation pattern at enhancer regions | Activation of BCL2 antiapoptotic gene | [56,57,58,59] |
Global H3 and H4 acetylation loss | KATs (such as CREBBP), HDACs and fusion proteins derived from genetic alterations (SLC12A6-NUTM1 or ZNF384-EP300) | Chromatin silencing through the imposition of a repressive state | Poor outcome, associated to loss of H4 acetylation Blockade of BIM Prednisolone treatment resistance in murine models with deficit of H3 acetylation (impairing Rgs16 or Dusp10 induction) | [58,60,61,62,63,64,65,66,67,68] |
Histone ubiquitination | ||||
H2BK120ub | BRE1 protein complex (including WAC and RNF20) | Promotes transcriptional elongation by facilitating H3 methylation | Presence of H2BK120ub residues mediates KMT2A and DOT1L activity, maintaining BCP-ALL progression | [69,70,71] |
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de Barrios, O.; Parra, M. Epigenetic Control of Infant B Cell Precursor Acute Lymphoblastic Leukemia. Int. J. Mol. Sci. 2021, 22, 3127. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063127
de Barrios O, Parra M. Epigenetic Control of Infant B Cell Precursor Acute Lymphoblastic Leukemia. International Journal of Molecular Sciences. 2021; 22(6):3127. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063127
Chicago/Turabian Stylede Barrios, Oriol, and Maribel Parra. 2021. "Epigenetic Control of Infant B Cell Precursor Acute Lymphoblastic Leukemia" International Journal of Molecular Sciences 22, no. 6: 3127. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063127