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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].
Gene Expression Profiling to Detect New Treatment Targets in Leukemia and Lymphoma: A Future Perspective
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Torsten Haferlach, Wolfgang Kern, Alexander Kohlmann
Another approach was described by Qian et al. (21) in therapy-related AML and myeloid cell lines focussing on CD34-positive selected cells. They were the first ones to define a specific pattern of gene expression for t-AML in comparison with other AML subtypes. The most discriminating genes were found to be involved in arrested differentiation of early progenitor cells. A higher expression of cell cycle control genes such as CCNA2, CCNE2, and CDC2 and genes for cell cycle checkpoints such as BUB1 or growth (Myc) were found. Furthermore, downregulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, EKLF) and overexpression of FLT3 was detected. The authors concluded that these genes may be further investigated for new targets and drugs in this very unfavourable subtype of AML.
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Published in Expert Opinion on Investigational Drugs, 2023
High Pl3K-AKT-mTOR signaling is frequently observed in T-ALL and can be caused by cellular events involving mutations in Pl3K or AKT, mutations and deletions of PTEN, or IL7R signaling mutations. These mutations are particularly observed in the TAL1 subgroup. Pl3K inhibitors have shown efficacy in growth cell inhibition and survival of T-ALL cell lines and in vitro studies in synergy with various chemotherapeutic agents [51]. Recently, dual Pl3K/mTOR inhibitors have also shown synergistic efficacy with chemotherapeutic agents [52]. Another synergistic approach targets both PI3K and NOTCH1 through treatment with PI3K/mTOR inhibition by upregulating NOTCH1 target genes such as MYC. The first generation of mTOR inhibitors, including rapamycin (sirolimus), RAD001 (everolimus), and CCI-779 (temsirolimus), has demonstrated efficacy in T-ALL [53]. However, the second generation of inhibitors was shown more efficient by interfering with more downstream Pl3K-AKT-mTOR signaling effectors (Figure 1). Dual inhibitors demonstrated more efficacy than Pl3K- or mTOR only inhibitors. Direct AKT inhibition also showed efficacy. Inhibitors, such as MK-2206 and AZD5363, demonstrate cytotoxic effect against T-ALL cells and synergy with steroids in cell samples from patients with T-ALL [54,55]. Current ongoing trials are indicated in Table 3.
Gene expression profiles and cytokine environments determine the in vitro proliferation and expansion capacities of human hematopoietic stem and progenitor cells
Published in Hematology, 2022
Roberto Dircio-Maldonado, Rosario Castro-Oropeza, Patricia Flores-Guzman, Alberto Cedro-Tanda, Fredy Omar Beltran-Anaya, Alfredo Hidalgo-Miranda, Hector Mayani
Evidence has been presented indicating that increased expression of GATA2 and TAL1 is involved in the transition from HSCs to erythroid progenitors [35]. In this regard, it is noteworthy that in our study, we found increased levels of GATA2 and TAL1 in EPCs. Interestingly, several genes involved in T and B cell development and function were upregulated in MPCs. In our study, we defined MPCs as CD34+ CD38+ CD45RA+ CD71- Lin- cells; however, we did not include any lymphoid antigen in the selection strategy. It has been shown that common lymphoid progenitors (CLPs) also express the CD34+ CD38+ CD45RA+ Lin- immunophenotype [34]; thus, it is possible that the population we identified as MPCs may also include CLPs.
Congenital thrombocytopenia associated with a heterozygous variant in the MEIS1 gene encoding a transcription factor essential for megakaryopoiesis
Published in Platelets, 2022
Orna Steinberg-Shemer, Naama Orenstein, Tanya Krasnov, Sharon Noy-Lotan, Nathaly Marcoux, Orly Dgany, Joanne Yacobovich, Oded Gilad, Evelyn Shabad, Lina Basel-Salmon, Hannah Tamary
In humans, MEIS1 is expressed in a number of stages of hematopoietic development, from HSC and progenitor cells to mature megakaryocytes; its expression levels are especially high in HSCs and in megakaryocytes [10]. MEIS1 expression is necessary for the megakaryocyte/erythroid lineage commitment [11]. In a human induced pluripotent stem cell (iPSC) model, homozygous deletion of MEIS1 impaired hematopoietic differentiation, megakaryocyte maturation and thrombopoiesis [12]. This iPSC model also showed the involvement of MEIS1 in the generation of hemogenic endothelial progenitors, through the regulation of TAL1 expression; while megakaryopoiesis and thrombopoiesis were mediated by FLI1 expression [12]. Interestingly, heterozygous MEIS1 deletion in human iPSCs also led to impaired hematopoietic differentiation, although to a lesser extent [12]. Yet, no hematopoietic phenotype was described in humans with heterozygous variants of MEIS1.