scholarly journals The Role of TAL1 in Hematopoiesis and Leukemogenesis

Acta Naturae ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 15-23 ◽  
Author(s):  
E. R. Vagapova ◽  
P. V. Spirin ◽  
T. D. Lebedev ◽  
V. S. Prassolov
Keyword(s):  
Transcription Factors ◽  
T Cell ◽  
Blood Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Formation ◽  
Myeloid Differentiation ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Cell Acute Lymphoblastic Leukemia

TAL1 (SCL/TAL1, T-cell acute leukemia protein 1) is a transcription factor that is involved in the process of hematopoiesis and leukemogenesis. It participates in blood cell formation, forms mesoderm in early embryogenesis, and regulates hematopoiesis in adult organisms. TAL1 is essential in maintaining the multipotency of hematopoietic stem cells (HSC) and keeping them in quiescence (stage G0). TAL1 forms complexes with various transcription factors, regulating hematopoiesis (E2A/HEB, GATA1-3, LMO1-2, Ldb1, ETO2, RUNX1, ERG, FLI1). In these complexes, TAL1 regulates normal myeloid differentiation, controls the proliferation of erythroid progenitors, and determines the choice of the direction of HSC differentiation. The transcription factors TAL1, E2A, GATA1 (or GATA2), LMO2, and Ldb1 are the major components of the SCL complex. In addition to normal hematopoiesis, this complex may also be involved in the process of blood cell malignant transformation. Upregulation of C-KIT expression is one of the main roles played by the SCL complex. Today, TAL1 and its partners are considered promising therapeutic targets in the treatment of T-cell acute lymphoblastic leukemia.

scholarly journals Aberrant GATA2 Activation in Pediatric B-Cell Acute Lymphoblastic Leukemia

2022 ◽  
Vol 9 ◽  
Author(s):  
Han Wang ◽  
Bowen Cui ◽  
Huiying Sun ◽  
Fang Zhang ◽  
Jianan Rao ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Transcriptome Sequencing ◽  
Lymphoblastic Leukemia ◽  
Myeloid Differentiation ◽  
Sequencing Data ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Topologically Associating Domains ◽  
Cell Acute Lymphoblastic Leukemia

GATA2 is a transcription factor that is critical for the generation and survival of hematopoietic stem cells (HSCs). It also plays an important role in the regulation of myeloid differentiation. Accordingly, GATA2 expression is restricted to HSCs and hematopoietic progenitors as well as early erythroid cells and megakaryocytic cells. Here we identified aberrant GATA2 expression in B-cell acute lymphoblastic leukemia (B-ALL) by analyzing transcriptome sequencing data obtained from St. Jude Cloud. Differentially expressed genes upon GATA2 activation showed significantly myeloid-like transcription signature. Further analysis identified several tumor-associated genes as targets of GATA2 activation including BAG3 and EPOR. In addition, the correlation between KMT2A-USP2 fusion and GATA2 activation not only indicates a potential trans-activating mechanism of GATA2 but also suggests that GATA2 is a target of KMT2A-USP2. Furthermore, by integrating whole-genome and transcriptome sequencing data, we showed that GATA2 is also cis activated. A somatic focal deletion located in the GATA2 neighborhood that disrupts the boundaries of topologically associating domains was identified in one B-ALL patient with GATA2 activation. These evidences support the hypothesis that GATA2 could be involved in leukemogenesis of B-ALL and can be transcriptionally activated through multiple mechanisms. The findings of aberrant activation of GATA2 and its molecular function extend our understanding of transcriptional factor dysregulation in B-ALL.

scholarly journals Advances of target therapy on NOTCH1 signaling pathway in T-cell acute lymphoblastic leukemia

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Ruyue Zheng ◽  
Menglin Li ◽  
Shujuan Wang ◽  
Yanfang Liu
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Signaling Pathway ◽  
Target Therapy ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Gene Mutations ◽  
Hematopoietic Stem ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

AbstractT-cell acute lymphoblastic leukemia (T-ALL) is one of the hematological malignancies. With the applications of chemotherapy regimens and allogeneic hematopoietic stem cell transplantation, the cure rate of T-ALL has been significantly improved. However, patients with relapsed and refractory T-ALL still lack effective treatment options. Gene mutations play an important role in T-ALL. The NOTCH1 gene mutation is the important one among these genetic mutations. Since the mutation of NOTCH1 gene is considered as a driving oncogene in T-ALL, targeting the NOTCH1 signaling patheway may be an effective option to overcome relapsed and refractory T-ALL. This review mainly summarizes the recent research advances of targeting on NOTCH1 signaling pathway in T-ALL.

scholarly journals Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia

Haematologica ◽  
2020 ◽  
pp. haematol.2019.245639
Author(s):  
Chujing Zhang ◽  
Stella Amanda ◽  
Cheng Wang ◽  
Tze King Tan ◽  
Muhammad Zulfaqar Ali ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Aldehyde Dehydrogenase ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals How to Combine the Two Landmark Treatment Methods—Allogeneic Hematopoietic Stem Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy Together to Cure High-Risk B Cell Acute Lymphoblastic Leukemia?

2020 ◽  
Vol 11 ◽  
Author(s):  
Mingming Zhang ◽  
He Huang
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has made tremendous progress in the last few decades and is increasingly being used worldwide. The success of haploidentical HSCT has made it possible to have “a donor for everyone”. Patients who received transplantation in remission may have a favorable outcome, while those who were transplanted in advanced stages of disease have a poor prognosis. Although chimeric antigen receptor T (CAR-T) cell therapy is currently a milestone in the immunotherapy of relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) and has demonstrated high remission rates in patients previously treated in multiple lines, the relatively high relapse rate remains a barrier to CAR-T cell therapy becoming an excellent cure option. Therefore, combining these two approaches (allo-HSCT and CAR-T cell therapy) is an attractive area of research to further improve the prognosis of R/R B-ALL. In this review, we will discuss the current clinical practices of combining allo-HSCT with CAR-T cell therapy based on available data, including CAR-T cells as a bridge to allo-HSCT for R/R B-ALL and CAR-T cell infusion for post-transplant relapse. We will further explore not only other possible ways to combine the two approaches, including CAR-T cell therapy to clear minimal residual disease peri-transplantation and incorporation of CAR technology to treat graft-versus-host disease, but also the potential of CAR-T cells as a part of allo-HSCT.

Role of the T-Cell Acute Lymphoblastic Leukemia Oncoprotein TLX1/HOX11 in Chromatin Dynamics and Gene Regulatory Networks.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 56-56
Author(s):  
Irene Riz ◽  
Kristin K. Baxter ◽  
Hyo Jung Lee ◽  
Reza Behnam ◽  
Teresa S. Hawley ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Dna Binding ◽  
Cell Fate ◽  
Malignant Transformation ◽  
Binding Sites ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Homeodomain proteins (homeoproteins) have long been recognized as powerful transcriptional regulators. Inappropriate expression of these transcription factors often leads to major developmental malformations or malignant transformation. The in vitro DNA binding sites of homeoproteins are short sequences that are widely distributed throughout the genome and some canonical binding sites have been shown to be functionally important at distances >20 kb away from the nearest transcription start site. In addition to DNA-binding activity, several homeoproteins have been demonstrated to interact with chromatin-modifying enzymes. For example, we and others have reported that the TLX1 homeoprotein of T-cell acute lymphoblastic leukemia (T-ALL) inhibits the PP1/PP2A serine/threonine phosphatases (I. Riz and R.G. Hawley, Oncogene 24: 5561–5575, 2005) and more recently have found that TLX1 modulates histone/transcription factor acetyltransferase CBP activity (I. Riz et al., Oncogene 26: 4115–4123, 2007). PP1/PP2A and CBP are complex molecular machines integrating diverse regulatory pathways that impact on cell survival, proliferation and differentiation outcomes. Organogenesis and malignant transformation - despite obvious differences - share a common requirement for high-order cooperativity of transcription factors and transcriptional cofactors in regulating the expression of multiple sets of genes executing cell fate shifts. Targeting key regulatory nodes in order to coordinately regulate multiple genes is a common strategy of virus induced cell-transformation: accordingly, PP1/PP2A and CBP are targeted by transforming viral proteins. The Groucho/TLE (transducin-like Enhancer-of-split) family of corepressors are another example of master regulators of cell fate; for instance, it was reported that triggering the MAPK signaling cascade inactivates TLE corepressors leading to coordinated derepression of a large number of genes involved in cell proliferation. We now demonstrate that TLX1 interferes with TLE1 repressive function. By streptavidin affinity-based precipitation of biotinylated recombinant TLX1 protein (TLX1 fused to a biotinylation peptide) we show in vivo interaction of TLX1 and TLE1 in several different cell types, including human T-ALL and neuroblastoma cells. Interaction of TLX1 with TLE1 occurs via an Engrailed homology 1 (Eh1)-like domain as documented by GST pull-down assays and laser scanning confocal microscopy. Transient transfection experiments indicate that TLX1 prevents TLE1-mediated repression of reporter genes. Furthermore, in the context of endogenous chromatin structure, TLX1 derepresses the bHLH transcription factor gene, ACSL1(HASH1), a well characterized target of the HES1/TLE1 repressor complex. The process requires direct interaction of TLX1 with TLE1 and binding of TLX1 to DNA, since a point mutation in the Eh1-like motif or deletion of the third helix of the TLX1 homeodomain abrogated the effect. Additional data to be presented suggest a long-range mechanism of transcriptional regulation by TLX1: we propose that “transcriptional activation” by TLX1 (and, by analogy, other homeoproteins that interact with TLE corepressors) results in part from the chaperoned redistribution of TLE corepressors from proximal promoter regions of target genes to distal chromatin regulatory sites.

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