scholarly journals E2A-PBX1 functions as a coactivator for RUNX1 in acute lymphoblastic leukemia

Blood ◽  
2020 ◽  
Vol 136 (1) ◽  
pp. 11-23 ◽  
Author(s):  
Wen-Chieh Pi ◽  
Jun Wang ◽  
Miho Shimada ◽  
Jia-Wei Lin ◽  
Huimin Geng ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Fate ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
Gene Activation ◽  
Chromosomal Translocation ◽  
Direct Interaction ◽  
Binding Activity ◽  
Specific Cell ◽  
Dna Binding Activity

Abstract E2A, a basic helix-loop-helix transcription factor, plays a crucial role in determining tissue-specific cell fate, including differentiation of B-cell lineages. In 5% of childhood acute lymphoblastic leukemia (ALL), the t(1,19) chromosomal translocation specifically targets the E2A gene and produces an oncogenic E2A-PBX1 fusion protein. Although previous studies have shown the oncogenic functions of E2A-PBX1 in cell and animal models, the E2A-PBX1–enforced cistrome, the E2A-PBX1 interactome, and related mechanisms underlying leukemogenesis remain unclear. Here, by unbiased genomic profiling approaches, we identify the direct target sites of E2A-PBX1 in t(1,19)–positive pre-B ALL cells and show that, compared with normal E2A, E2A-PBX1 preferentially binds to a subset of gene loci cobound by RUNX1 and gene-activating machineries (p300, MED1, and H3K27 acetylation). Using biochemical analyses, we further document a direct interaction of E2A-PBX1, through a region spanning the PBX1 homeodomain, with RUNX1. Our results also show that E2A-PBX1 binding to gene enhancers is dependent on the RUNX1 interaction but not the DNA-binding activity harbored within the PBX1 homeodomain of E2A-PBX1. Transcriptome analyses and cell transformation assays further establish a significant RUNX1 requirement for E2A-PBX1–mediated target gene activation and leukemogenesis. Notably, the RUNX1 locus itself is also directly activated by E2A-PBX1, indicating a multilayered interplay between E2A-PBX1 and RUNX1. Collectively, our study provides the first unbiased profiling of the E2A-PBX1 cistrome in pre-B ALL cells and reveals a previously unappreciated pathway in which E2A-PBX1 acts in concert with RUNX1 to enforce transcriptome alterations for the development of pre-B ALL.

scholarly journals Preferred sequences for DNA recognition by the TAL1 helix-loop-helix proteins.

1994 ◽  
Vol 14 (2) ◽  
pp. 1256-1265 ◽  
Author(s):  
H L Hsu ◽  
L Huang ◽  
J T Tsan ◽  
W Funk ◽  
W E Wright ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Dna Binding ◽  
Lymphoblastic Leukemia ◽  
Dna Recognition ◽  
Binding Activity ◽  
Class A ◽  
Helix Loop Helix ◽  
Dna Binding Activity ◽  
Cell Acute Lymphoblastic Leukemia

Tumor-specific activation of the TAL1 gene is the most common genetic alteration seen in patients with T-cell acute lymphoblastic leukemia. The TAL1 gene products contain the basic helix-loop-helix (bHLH) domain, a protein dimerization and DNA-binding motif common to several known transcription factors. A binding-site selection procedure has now been used to evaluate the DNA recognition properties of TAL1. These studies demonstrate that TAL1 polypeptides do not have intrinsic DNA-binding activity, presumably because of their inability to form bHLH homodimers. However, TAL1 readily interacts with any of the known class A bHLH proteins (E12, E47, E2-2, and HEB) to form heterodimers that bind DNA in a sequence-specific manner. The TAL1 heterodimers preferentially recognize a subset of E-box elements (CANNTG) that can be represented by the consensus sequence AACAGATGGT. This consensus is composed of half-sites for recognition by the participating class A bHLH polypeptide (AACAG) and the TAL1 polypeptide (ATGGT). TAL1 heterodimers with DNA-binding activity are readily detected in nuclear extracts of Jurkat, a leukemic cell line derived from a patient with T-cell acute lymphoblastic leukemia. Hence, TAL1 is likely to bind and regulate the transcription of a unique subset of subordinate target genes, some of which may mediate the malignant function of TAL1 during T-cell leukemogenesis.

Preferred sequences for DNA recognition by the TAL1 helix-loop-helix proteins

1994 ◽  
Vol 14 (2) ◽  
pp. 1256-1265
Author(s):  
H L Hsu ◽  
L Huang ◽  
J T Tsan ◽  
W Funk ◽  
W E Wright ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Dna Binding ◽  
Lymphoblastic Leukemia ◽  
Dna Recognition ◽  
Binding Activity ◽  
Class A ◽  
Helix Loop Helix ◽  
Dna Binding Activity ◽  
Cell Acute Lymphoblastic Leukemia

Tumor-specific activation of the TAL1 gene is the most common genetic alteration seen in patients with T-cell acute lymphoblastic leukemia. The TAL1 gene products contain the basic helix-loop-helix (bHLH) domain, a protein dimerization and DNA-binding motif common to several known transcription factors. A binding-site selection procedure has now been used to evaluate the DNA recognition properties of TAL1. These studies demonstrate that TAL1 polypeptides do not have intrinsic DNA-binding activity, presumably because of their inability to form bHLH homodimers. However, TAL1 readily interacts with any of the known class A bHLH proteins (E12, E47, E2-2, and HEB) to form heterodimers that bind DNA in a sequence-specific manner. The TAL1 heterodimers preferentially recognize a subset of E-box elements (CANNTG) that can be represented by the consensus sequence AACAGATGGT. This consensus is composed of half-sites for recognition by the participating class A bHLH polypeptide (AACAG) and the TAL1 polypeptide (ATGGT). TAL1 heterodimers with DNA-binding activity are readily detected in nuclear extracts of Jurkat, a leukemic cell line derived from a patient with T-cell acute lymphoblastic leukemia. Hence, TAL1 is likely to bind and regulate the transcription of a unique subset of subordinate target genes, some of which may mediate the malignant function of TAL1 during T-cell leukemogenesis.

scholarly journals Colony formation in vitro by leukemic cells in acute lymphoblastic leukemia (ALL)

Blood ◽  
1978 ◽  
Vol 52 (4) ◽  
pp. 712-718 ◽  
Author(s):  
SD Smith ◽  
EM Uyeki ◽  
JT Lowman
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Cells ◽  
Lymphoblastic Leukemia ◽  
Lymphoid Cells ◽  
Assay System ◽  
Leukemic Cells ◽  
Specific Cell ◽  
Specific Cell Surface

Abstract An assay system in vitro for the growth of malignant lymphoblastic colony-forming cells (CFC) was established. Growth of malignant myeloblastic CFC has been previously reported, but this is the first report of growth of malignant lymphoblastic CFC. Established assay systems in vitro have been very helpful in elucidating the control of growth and differentiation of both normal and malignant bone marrow cells. Lymphoblastic CFC were grown from the bone marrow aspirates of 20 children with acute lymphoblastic leukemia. Growth of these colonies was established on an agar assay system and maintained in the relative hypoxia (7% oxygen) of a Stulberg chamber. The criteria for malignancy of these colonies was based upon cellular cytochemical staining characteristics, the presence of specific cell surface markers, and the ability of these lymphoid cells to grow without the addition of a lymphoid mitogen. With this technique, specific nutritional requirements and drug sensitivities can be established in vitro, and these data may permit tailoring of individual antileukemic therapy.

The Drosophila extramacrochaetae protein antagonizes sequence-specific DNA binding by daughterless/achaete-scute protein complexes

Development ◽  
1991 ◽  
Vol 113 (1) ◽  
pp. 245-255 ◽  
Author(s):  
M. Van Doren ◽  
H.M. Ellis ◽  
J.W. Posakony
Keyword(s):  
Dna Binding ◽  
Cell Fate ◽  
Protein Complexes ◽  
Competitive Inhibitor ◽  
Binding Activity ◽  
Regulatory Function ◽  
Biochemical Basis ◽  
Dna Binding Activity

In Drosophila, a group of regulatory proteins of the helix-loop-helix (HLH) class play an essential role in conferring upon cells in the developing adult epidermis the competence to give rise to sensory organs. Proteins encoded by the daughterless (da) gene and three genes of the achaete-scute complex (AS-C) act positively in the determination of the sensory organ precursor cell fate, while the extramacrochaetae (emc) and hairy (h) gene products act as negative regulators. In the region upstream of the achaete gene of the AS-C, we have identified three ‘E box’ consensus sequences that are bound specifically in vitro by hetero-oligomeric complexes consisting of the da protein and an AS-C protein. We have used this DNA-binding activity to investigate the biochemical basis of the negative regulatory function of emc. Under the conditions of our experiments, the emc protein, but not the h protein, is able to antagonize specifically the in vitro DNA-binding activity of da/AS-C and putative da/da protein complexes. We interpret these results as follows: the heterodimerization capacity of the emc protein (conferred by its HLH domain) allows it to act in vivo as a competitive inhibitor of the formation of functional DNA-binding protein complexes by the da and AS-C proteins, thereby reducing the effective level of their transcriptional regulatory activity within the cell.

scholarly journals miR-22-3p Negatively Affects Tumor Progression in T-Cell Acute Lymphoblastic Leukemia

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1726
Author(s):  
Valentina Saccomani ◽  
Angela Grassi ◽  
Erich Piovan ◽  
Deborah Bongiovanni ◽  
Ludovica Di Martino ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Target Genes ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
T Cell Development ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Signaling Pathway

T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive disease arising from T-cell precursors. NOTCH1 plays an important role both in T-cell development and leukemia progression, and more than 60% of human T-ALLs harbor mutations in components of the NOTCH1 signaling pathway, leading to deregulated cell growth and contributing to cell transformation. Besides multiple NOTCH1 target genes, microRNAs have also been shown to regulate T-ALL initiation and progression. Using an established mouse model of T-ALL induced by NOTCH1 activation, we identified several microRNAs downstream of NOTCH1 activation. In particular, we found that NOTCH1 inhibition can induce miR-22-3p in NOTCH1-dependent tumors and that this regulation is also conserved in human samples. Importantly, miR-22-3p overexpression in T-ALL cells can inhibit colony formation in vitro and leukemia progression in vivo. In addition, miR-22-3p was found to be downregulated in T-ALL specimens, both T-ALL cell lines and primary samples, relative to immature T-cells. Our results suggest that miR-22-3p is a functionally relevant microRNA in T-ALL whose modulation can be exploited for therapeutic purposes to inhibit T-ALL progression.

scholarly journals Erk Negative Feedback Control Enables Pre-B Cell Transformation and Represents a Therapeutic Target in Acute Lymphoblastic Leukemia

Cancer Cell ◽  
2015 ◽  
Vol 28 (1) ◽  
pp. 114-128 ◽  
Author(s):  
Seyedmehdi Shojaee ◽  
Rebecca Caeser ◽  
Maike Buchner ◽  
Eugene Park ◽  
Srividya Swaminathan ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Feedback Control ◽  
B Cell ◽  
Negative Feedback ◽  
Therapeutic Target ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
Negative Feedback Control

scholarly journals TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4252-4258 ◽  
Author(s):  
TW McLean ◽  
S Ringold ◽  
D Neuberg ◽  
K Stegmaier ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Polymerase Chain ◽  
B Lineage

Abstract Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co- immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.

A new complex chromosomal translocation t(2;12;21)(q33;p13;q22) in B-cell acute lymphoblastic leukemia

2006 ◽  
Vol 168 (2) ◽  
pp. 179-180 ◽  
Author(s):  
E.A. Vasquez-Jimenez ◽  
E.J. Romo-Martínez ◽  
J.P. Meza-Espinoza ◽  
B. Lopez-Guido ◽  
M.T. Magaña-Torres ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Cell Acute Lymphoblastic Leukemia

E2a-Pbx1 Direct Targets and Secondary Mutations in Leukemogenesis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3343-3343
Author(s):  
Christofer Diakos ◽  
Yuanyuan Xiao ◽  
Jerry Hofmann ◽  
Shichun Zheng ◽  
Michelle Kang ◽  
...  
Keyword(s):  
Target Genes ◽  
Cell Transformation ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Gene Promoter ◽  
Transactivation Domain ◽  
Oncogenic Potential ◽  
Expression Arrays ◽  
Functional Regulation ◽  
Copy Number Changes

Abstract E2a-Pbx1 is expressed as a result of the t(1;19) chromosomal translocation in nearly 5% of cases of acute lymphoblastic leukemia. The E2a-Pbx1 chimeric transcription factor contains the N-terminal transactivation domain of E2A fused to the C-terminal DNAbinding homeodomain of Pbx1. Previews studies indicate that additional genetic events may be required for E2A-Pbx1-leukemic transformation, based on long incubation times and monoclonal nature of tumors observed in mouse models. While there is no doubt of its oncogenic potential, the mechanisms of E2a-Pbx1-mediated pre-B cell transformation and the nature of direct E2a-Pbx1 target genes and additional events that complement the fusion oncogene to create full-blown leukemia are still unclear. Herein we used chromatin immunoprecipitation (ChIP-chip) assays to identify direct targets of E2a-Pbx1, and we used gene and miRNA expression arrays of siRNA E2a-Pbx1-silenced cells to evaluate changes in expression induced by the fusion protein. To identify complementary genetic rearrangements, analyses of primary E2a-Pbx1 leukemias were performed to copy number changes and loss of heterozygosity which might identify mutations that synergize with the direct/functional E2a-Pbx1 targets to produce the leukemic phenotype. These arrays were analyzed in comparison to high-density gene promoter methylation arrays. Our data identified members of the WNT pathway as direct targets of E2a-Pbx1. Expression data from E2a-Pbx1 silenced cells support this finding as they demonstrate a functional regulation of this pathway. We further show a differential impact of E2a-Pbx1 silencing on the miRNA profile and identify E2a-Pbx1 dependent miRNAs. Using CGH arrays on primary E2a-Pbx1 samples we were able to pinpoint candidate secondary mutations as well as broad genetic categories: cases with 1q+, 1q+ combined with 9p-, and, separately, cases with +8. In summary we present direct and functional E2a-Pbx1 targets as well as candidate secondary mutations. We propose a model were direct and functional E2a- Pbx1 driven pathways that might include both genes and miRNAs might collaborate with identified auxiliary events to produce the E2a-Pbx1 leukemia.

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