Molecular Analysis of Evi1, a Zinc Finger Oncogene Involved in Myeloid Leukemia

1996 ◽  
pp. 211-222 ◽  
Author(s):  
M. C. Lopingco ◽  
A. S. Perkins
Keyword(s):  
Zinc Finger ◽  
Molecular Analysis ◽  
Myeloid Leukemia

scholarly journals The ETO Protein Disrupted in t(8;21)-Associated Acute Myeloid Leukemia Is a Corepressor for the Promyelocytic Leukemia Zinc Finger Protein

2000 ◽  
Vol 20 (6) ◽  
pp. 2075-2086 ◽  
Author(s):  
Ari M. Melnick ◽  
Jennifer J. Westendorf ◽  
Adam Polinger ◽  
Graeme W. Carlile ◽  
Sally Arai ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Zinc Finger ◽  
Transcriptional Repression ◽  
Histone Deacetylases ◽  
Myeloid Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Promyelocytic Leukemia ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Acute Myeloid

ABSTRACT The ETO protein was originally identified by its fusion to the AML-1 transcription factor in translocation (8;21) associated with the M2 form of acute myeloid leukemia (AML). The resulting AML-1–ETO fusion is an aberrant transcriptional regulator due to the ability of ETO, which does not bind DNA itself, to recruit the transcriptional corepressors N-CoR, SMRT, and Sin3A and histone deacetylases. The promyelocytic leukemia zinc finger (PLZF) protein is a sequence-specific DNA-binding transcriptional factor fused to retinoic acid receptor α in acute promyelocytic leukemia associated with the (11;17)(q23;q21) translocation. PLZF also mediates transcriptional repression through the actions of corepressors and histone deacetylases. We found that ETO is one of the corepressors recruited by PLZF. The PLZF and ETO proteins associate in vivo and in vitro, and ETO can potentiate transcriptional repression by PLZF. The N-terminal portion of ETO forms complexes with PLZF, while the C-terminal region, which was shown to bind to N-CoR and SMRT, is required for the ability of ETO to augment transcriptional repression by PLZF. The second repression domain (RD2) of PLZF, not the POZ/BTB domain, is necessary to bind to ETO. Corepression by ETO was completely abrogated by histone deacetylase inhibitors. This identifies ETO as a cofactor for a sequence-specific transcription factor and indicates that, like other corepressors, it functions through the action of histone deactylase.

scholarly journals Molecular analysis of interferon-induced suppression of Philadelphia chromosome in patients with chronic myeloid leukemia

Blood ◽  
1987 ◽  
Vol 69 (3) ◽  
pp. 961-963 ◽  
Author(s):  
G Yoffe ◽  
M Blick ◽  
H Kantarjian ◽  
G Spitzer ◽  
J Gutterman ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Myeloid Leukemia ◽  
Clinical Course ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Human Interferon ◽  
Complete Suppression ◽  
Complete Disappearance ◽  
Course Of Disease ◽  
Normal Bone

Treatment with recombinant human interferon alpha-A (Roferon-A) is associated with stable suppression of the population of cells that display the Philadelphia (Ph1) chromosome in some patients with chronic myelogenous leukemia (CML) as defined by cytogenetic analysis. Southern blot analyses employing a 3′ breakpoint cluster region (bcr) probe (Pr- 1) were performed to confirm a complete suppression of the Ph1+ chromosome-positive clone of cells at the DNA level. The complete disappearance of rearranged restriction fragments of the bcr gene, which were a characteristic of the disease prior to Roferon-A therapy, was accompanied by the restoration of normal bone marrow and achievement of durable ongoing complete remission for 9 and 6 months, respectively, in two patients with Philadelphia-positive (Ph1+) CML. Molecular analysis is a valuable probe for monitoring the clinical course of disease in patients with Ph1+ CML.

muscleblind, a gene required for photoreceptor differentiation in Drosophila, encodes novel nuclear Cys3His-type zinc-finger-containing proteins

Development ◽  
1997 ◽  
Vol 124 (21) ◽  
pp. 4321-4331 ◽  
Author(s):  
G. Begemann ◽  
N. Paricio ◽  
R. Artero ◽  
I. Kiss ◽  
M. Perez-Alonso ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Zinc Finger ◽  
Molecular Analysis ◽  
Neural Differentiation ◽  
General Factor ◽  
Lethal Gene ◽  
Zinc Finger Motif ◽  
Embryonic Lethal ◽  
Phenotype Analysis ◽  
Mutant Cells

We have isolated the embryonic lethal gene muscleblind (mbl) as a suppressor of the sev-svp2 eye phenotype. Analysis of clones mutant for mbl during eye development shows that it is autonomously required for photoreceptor differentiation. Mutant cells are recruited into developing ommatidia and initiate neural differentiation, but they fail to properly differentiate as photoreceptors. Molecular analysis reveals that the mbl locus is large and complex, giving rise to multiple different proteins with common 5′ sequences but different carboxy termini. Mbl proteins are nuclear and share a Cys3His zinc-finger motif which is also found in the TIS11/NUP475/TTP family of proteins and is highly conserved in vertebrates and invertebrates. Functional analysis of mbl, the observation that it also dominantly suppresses the sE-Jun(Asp) gain-of-function phenotype and the phenotypic similarity to mutants in the photoreceptor-specific glass gene suggest that mbl is a general factor required for photoreceptor differentiation.

scholarly journals Molecular analysis of odd-skipped, a zinc finger encoding segmentation gene with a novel pair-rule expression pattern.

1990 ◽  
Vol 9 (11) ◽  
pp. 3795-3804 ◽  
Author(s):  
D. E. Coulter ◽  
E. A. Swaykus ◽  
M. A. Beran-Koehn ◽  
D. Goldberg ◽  
E. Wieschaus ◽  
...  
Keyword(s):  
Expression Pattern ◽  
Zinc Finger ◽  
Molecular Analysis ◽  
Segmentation Gene ◽  
Pair Rule

A cytogenetic and molecular analysis of five variant Philadelphia translocations in chronic myeloid leukemia

1988 ◽  
Vol 35 (2) ◽  
pp. 179-197 ◽  
Author(s):  
Christine M. Morris ◽  
Ingrid Rosman ◽  
Susan A. Archer ◽  
Jill M. Cochrane ◽  
Peter H. Fitzgerald
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Molecular Analysis ◽  
Myeloid Leukemia

The Genomic Landscape of Wilms' Tumor 1 (WT1) Mutant Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
Hassan Awada ◽  
Arda Durmaz ◽  
Carmelo Gurnari ◽  
Misam Zawit ◽  
Sunisa Kongkiatkamon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Zinc Finger ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Deletion Syndrome ◽  
Wt1 Gene ◽  
Genomic Landscape ◽  
Wilms Tumor 1 ◽  
Acute Myeloid

Mutations in tumor suppressor genes and oncogenes are both potentially therapeutically actionable in acute myeloid leukemia (AML). The Wilms' Tumor 1 (WT1) gene is located on 11p13 and encodes a zinc finger transcription factor which has been found to be overexpressed and mutated in AML. In normal development, WT1 is only expressed in a small subset of hematopoietic stem cells. While its overexpression suggests an oncogenic role, the invariable presence of mutations in the cysteine-histidine zinc finger domains indicates a tumor suppressor function, similar to that in WAGR syndrome/11p deletion syndrome in which it was first discovered. Like its unknown function in AML, the clinical significance and genetic associations of WT1 mutations have been also controversial. Although studies of WT1 mutations in AML have been conducted, the lack of solid clinical and molecular characterization of large WT1-mutant (WT1MT) AML cohort has hampered its definition. In this study, we took advantage of a compendia of genomic results from Cleveland Clinic and publicly available data of 2188 AML patients (primary (p)AML, n= 1636; secondary (s)AML, n= 433; therapy-related (t)AML, n= 119, excluding cases with acute promyelocytic leukemia, MLL-rearrangement, and core-binding factor AML). While several reports only focused on cytogenetic normal AML (CN-AML), which represented 61% of our cohort, we additionally included all other cytogenetic risk groups. In total, WT1 mutations were detected in 5% (114/2188) of patients. WT1 mutations were enriched in pAML (85%) compared to sAML (11%) and tAML (4%). Thirty-nine patients (13%) carried more than 1 WT1 mutation. WT1MT were younger [59 vs 64 years, P=0.0002] and more often females (55% vs 45%, P=0.03) as compared to WT1 wild type (WT1WT) patients. Univariate analyses of baseline parameters showed that WT1MT AML had a more proliferative phenotype with a higher WBC [15.1 vs 9.5 x109/L, P=0.03] and bone marrow blast percentages [73 vs 59%, P=0.002] and with lower platelet counts [44 vs 56 x109/L, P=0.008] compared to WT1WT cases. In the WT1MT cohort, 70% had a normal karyotype, with complex karyotype being significantly less frequent vsWT1WT patients [4 vs 16%, P=0.001]. The most common cytogenetic abnormalities in WT1MT patients included +8 (8%) followed by -9/del(9q) (3%) and -7/del(7q) (3%). Only 1 patient carried inv(3)/t(3;3) or -17/del(17p). In sum, no statistical differences in cytogenetics were found between WT1MTvsWT1WT AML patients. Next, identified mutational signatures of WT1MT patients. A panel of 44 myeloid genes and their hotspot configurations were selected according to their relevance in AML. In comparison to WT1WT AML patients, multivariate analyses showed that WT1MT patients had higher odds of biallelic CEBPA (12 vs 3%; P=0.009) and FLT3 internal tandem duplication mutations (FLT3ITD, 31 vs 16%; P=0.01) but lower odds of SRSF2 mutations (2 vs 9%, P=0.04). Since FLT3ITD has been previously described to be associated with WT1 mutations, we also focused on investigating whether mutations in the tyrosine kinase domain (TKD) were frequent in WT1MT as well. Although we found increased percentages of FLT3TKD (11%) among the WT1MT patients compared to WT1WT cohort (8%), this difference did not reach statistical significance. To uncover multifactor lesions (cytogenetic and/ or additional molecular lesions) of prognostic importance, we performed survival analyses. Although the combination of WT1 mutations and FLT3TKD shortened overall survival (OS) by 2-times in WT1MT patients vsWT1WT cases with FLT3TKD (23.7 vs 45.9 months), this result was not significant (P=0.1). In addition, the concurrent presence of other cytogenetic and molecular features didn't reveal significant impact on OS. In sum, using an adequately powered cohort, our study of the genomic landscape of WT1MT AML patients identified its genomic associations and their clinical and prognostic inferences. The application of advanced machine learning methods to large datasets of WT1MT AML patients might be crucial to capture the complex genomic interactions of WT1 gene in AML. Disclosures Carraway: BMS: Consultancy, Other: Research support, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Abbvie: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Nazha:MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Jazz: Research Funding. Sekeres:Pfizer: Consultancy; BMS: Consultancy; Takeda/Millenium: Consultancy. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

scholarly journals GATA2 zinc finger 2 mutation found in acute myeloid leukemia impairs myeloid differentiation

2013 ◽  
Vol 2 (1) ◽  
pp. 21-25 ◽  
Author(s):  
Keiko Niimi ◽  
Hitoshi Kiyoi ◽  
Yuichi Ishikawa ◽  
Fumihiko Hayakawa ◽  
Shingo Kurahashi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Zinc Finger ◽  
Myeloid Leukemia ◽  
Myeloid Differentiation ◽  
Acute Myeloid
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