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Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
About half of all patients diagnosed with T-ALL demonstrate the presence of chromosomal translocations involving 14q11 (T-cell receptor [TCR] α and δ genes) and 7q34 regions, juxtaposing the TCR genes to one of several transcriptional factors, such as TAL1, TAL2, TLX1 (HOX11), TLX3, NKX2-1, NKX2-5, HOXA, MYC, MYB, LYL1, OLIG2, LMO2, and others. Research has shown a pivotal role of the NOTCH1-MYC signaling and also the potential oncogenic role of RUNX1 in the early initiation of T-ALL. Some patients with T-ALL harbor rearrangements of ABL1, such as EML1-ABL1 and ETV6-ABL1, and may be candidates for ABL tyrosine kinase inhibitors (TKIs). A distinct subtype of T-ALL, ETP-ALL has also been characterized genetically. It accounts for about 15% of all T-ALL in children and about 35% in adults and involves multiple keynote cellular pathways, including RUNX1, IKZF1, ETV6, GATA3, and EP300, that are involved in hematopoiesis. Some of these patients also demonstrate involvement of JAK-STAT and PRC2 pathways and may benefit from JAK inhibitors or chromatin-modifying agents, respectively.39
GATA2 Deficiency
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Expressed in mature megakaryocytes, mast cells, and monocytes, GATA2 binds directly to the consensus DNA sequence (A/T)GATA(A/G)GATA2 in its downstream effectors (e.g., SPI1, FLI1, TAL1, LMO2, RUNX1, GATA1, and CEBPA) via its two highly conserved zinc finger domains. Specifically, GATA2 forms a core heptad regulatory unit (consisting GATA2, TAL1, LYL1, LMO2, ERG, FLI1, and RUNXI) that is found over 1000 loci in primitive hematopoietic cells, and plays an essential role in the proliferation and differentiation of HSC, including the endothelial to hematopoietic transition (yielding the first adult HSC) in embryo and HSC survival and self-renewal in adult hematopoiesis [12].
Acute Lymphoblastic Leukaemia
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
About half of all patients diagnosed with T-ALL demonstrate the presence of chromosomal translocations involving 14q11 (T-cell receptor [TCR] α and δ genes) and 7q34 regions, juxtaposing the TCR genes to one of several transcriptional factors, such as TAL1, TAL2, TLX1 (HOX11), TLX3, NKX2-1, NKX2-5, HOXA, MYC, MYB, LYL1, OLIG2, LMO2 and others. Research has also shown a pivotal role of the NOTCH1-MYC signalling, and also the potential oncogenic, rather than tumour suppressive, role of RUNX1 in the early initiation of T-ALL. There are also reports of some patients with T-ALL harbour rearrangements of ABL1, such as EML1-ABL1 and ETV6-ABL1, and may be candidates for ABL tyrosine kinase inhibitors (TKIs). Research has demonstrated several novel abnormalities which may also be amenable to targeted agents in early development. For example, somatic mutations and copy number alterations have been observed in NOTCH1, MYB and FBXW7 genes; the JAK-STAT and RAS/PI3K/AKT and epigenetic pathways, have been noted to be involved in some patients with T-ALL.
Bioinformatics analysis deciphering the transcriptomic signatures associated with signalling pathways and prognosis in the myelodysplastic syndromes
Published in Hematology, 2022
Niluopaer Tuerxun, Jie Wang, Fang Zhao, Yu-ting Qin, Huan Wang, Rong Chen, Jian-ping Hao
In the integrated datasets, we explored 2404 differentially expressed genes (DEGs), which included 1619 upregulated (Supplementary Table S1) and 785 downregulated (Supplementary Table S2) genes in the MDS datasets when compared with healthy control. The top (the highest combined effect size (ES)) significantly upregulated 25 genes (such as DENND2D, SMIM20, KCNE3, TGDS, ALDH3B1, SNX3, PLEKHA8P1, CDC16, E2F6, RPS27L, COA6, LYL1, BNIP3, and CHCHD10) are displaying in Table 1. In addition, the top 25 downregulated genes (such as OR7A5, GPR176, IRF4, ARPP21, IGHV5-78, LRIG1, AKAP12, DUSP26, MME, RAG1, SH2D4B, and LDLRAD4) are displayed in Table 2.
Targeting ubiquitin protein ligase E3 component N-recognin 5 in cancer cells induces a CD8+ T cell mediated immune response
Published in OncoImmunology, 2020
Mei Song, Chao Wang, Huan Wang, Tuo Zhang, Jiuqi Li, Robert Benezra, Lotfi Chouchane, Yin-Hao Sun, Xin-Gang Cui, Xiaojing Ma
In contrast to the strong paracrine involvement of CD8+ T-mediated immunity in UBR5-regulated tumor growth, the metastatic process driven by UBR5 appears to be primarily cell-intrinsic. Our data demonstrate that the annulling of Ubr5 in 4T1 cells is causative for the loss of E-cadherin expression and impairs the tumor cells’ mesenchymal to epithelial transition (MET) and their ability to colonize in secondary organs. This effect is controlled by UBR5 principally through transcriptional regulation of the key EMT regulators ID1 and ID3. The result is the maintenance of Ubr5−/- tumor cells in the mesenchymal state lacking E-cadherin expression, thus unable to complete MET and take roots in the lungs. It is thus of great importance to further understand how UBR5 loss leads to ID1/ID3 downregulation. Given the mechanism of UBR5’s action, it is possible that loss of UBR5 may lead to the stabilization of a repressor which inhibits ID1/ID3 expression. ATF3 is a well-characterized, known repressor of ID1 expression.24 It will be interesting to determine if UBR5 destabilizes ATF3. It is equally possible that loss of UBR5 leads indirectly to the loss of a positively acting transcription factor that controls ID1/ID3 expression. A variety of factors that control ID1 expression in TNBC cells have been identified. The basic helix-loop-helix (bHLH) transcription factor Lyl1 and CREB1, a widely expressed transcription factor, and a suspected oncogene, interact and form a molecular complex. The histone acetyltransferases p300 and CBP are recruited to this complex. Together they activate CREB1 target promoters such as Id1, Id3, cyclin D3, Brca1, Btg2, and Egr1.25
The genomic and biological complexity of mixed phenotype acute leukemia
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Claire Andrews, Anne Tierens, Mark Minden
The largest pediatric MPAL study, by Mullighan’s group at the St Jude Comprehensive Cancer Center, utilized full exome, transcriptome and/or whole genome sequencing for 115 patients [4]. As in adults, genes recurrently mutated in AML were altered in some MPAL; these included FLT3, RUNX1 and CEBPA, but no DNMT3a mutations, in keeping with its association with aging. As well, mutations that recurrently were observed in ALL, including CDKN2A, CDKN2B, ETV6 and VPBEB1, were present in pediatric MPAL. In the case of T-MPAL, abnormalities of core transcription factors such as TAL2, LMO1, LMO2, LYL1 occurred, but at a lower frequency compared to T-ALL (16% vs 63%); of note, no TAL1 abnormalities were found in T-MPAL. Finally, WT1 and KMT2A mutations that occur in both AML and ALL were mutated in T-MPAL at a higher frequency than in T-ALL (41% vs 9%). Remarkably, rearrangement of ZNF384 was found in 48% of cases of B-myeloid MPAL. Given this high incidence, the authors suggested recognition of this abnormality as a separate entity in the WHO classification of MPAL. Interestingly, the gene expression profiles of ZNF384r MPAL and childhood ZNF384r B-ALL were indistinguishable. One of the highly expressed genes associated with ZNF384r is the wild type FLT3, which could have therapeutic implications if a FLT3 inhibitor were to be added to the therapy for this form of MPAL [4]. Interestingly, rearrangement of ZNF384 is reported rarely in adults, which suggests that a different cell of origin or biologic process may occur predominantly in children [5,6]; this is supported by the observation of differences in biology and therapeutic response between pediatric and adult patients [38,39].