Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ikaros is a zinc-finger transcriptional factor playing an essential role in lymphoid lineage commitment and differentiation. Animal models and analysis of human Ikaros in leukemic cells demonstrate deregulation of Ikaros expression. Short isoforms with a truncated DNA-binding domain suppress functions of Ikaros in a dominant-negative manner. Previous studies demonstrated that human leukemias are heterogeneous for Ikaros expression. We estimate the relative level of Ikaros mRNA transcripts in 80 childhood ALL cases in comparison with AML and healthy donor groups. We detected eight major isoforms and several minor mutant isoforms in most patients with acute lymphoblastic and myeloid leukemia and in healthy donors, but the relative level of expression varied. The relatively high level of Ik4A isoform, rarely mentioned in previous reports, was detected in all analyzed groups. The ratio between functional and all isoforms was used to determine functional activity of Ikaros. The ratio was significantly less in AML (p=0.027) and BCR-ABL positive ALL (p=0.0028) than in healthy bone marrow. We found a negative association between the Ikaros ratio and myeloid coexpression in B-cell ALL, the most prominent was for CD15. The Ikaros ratio positively correlates with CD5 and negatively with CD7 expression in T-ALL. We suggest that an anti-proliferation and anti-activation effect of full-length Ikaros may be mediated through regulation of CD5 and CD7.
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PMID:Relative expression of different Ikaros isoforms in childhood acute leukemia. 1867 65

Childhood acute lymphoblastic leukaemia (ALL) is a heterogenous disease in which oncogene fusion transcripts are known to influence the biological behaviour of the different ALL subtypes. Screening for prognostically important transcripts is an important diagnostic step in treatment stratification and prognostication of affected patients. We describe a SYBR-Green real-time multiplex PCR assay to screen for transcripts TEL-AML1, E2A-PBX1, MLL-AF4, and the two breakpoints of BCR-ABL (p190 and p210). Validation of the assay was based on conventional karyotyping results. This new assay provides a rapid, sensitive, and accurate detection method for prognostically important transcripts in childhood ALL.
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PMID:Rapid detection of prognostically important childhood acute lymphoblastic leukemia chimeric transcripts using multiplex SYBR green real-time reverse transcription PCR. 1898 26

PAX5, a master regulator of B-cell development, was recently shown to be involved in several leukemia-associated rearrangements, which result in fusion genes encoding chimeric proteins that antagonize PAX5 transcriptional activity. In a population-based fluorescence in situ hybridization screening study of 446 childhood acute lymphoblastic leukemia (ALL) patients, we now show that PAX5 rearrangements occur at an incidence of about 2.5% of B-cell precursor ALL. Identification of several novel PAX5 partner genes, including POM121, BRD1, DACH1, HIPK1 and JAK2 brings the number of distinct PAX5 in-frame fusions to at least 12. Our data show that these not only comprise transcription factors but also structural proteins and genes involved in signal transduction, which at least in part have not been implicated in tumorigenesis.
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PMID:Incidence and diversity of PAX5 fusion genes in childhood acute lymphoblastic leukemia. 1902 May 46

The role of BCR/ABL isoforms and their relationship to leukemia phenotype have been of major concern. Atypical BCR/ABL mRNA transcripts lacking exon a2 have been reported in 12 cases of acute lymphoblastic leukemia (ALL) to date; among them, a b3a3 type transcript has been reported only once in the childhood ALL. Reported here is the case of a patient with Philadelphia-positive (Ph(+)) ALL expressing a b3a3 type transcript, a rare type of BCR/ABL mRNA lacking ABL exon a2 sequences. Bone marrow showed a hypercellular marrow with leukemic blasts positive for CD10, CD19, CD79a, and cytoplasmic mu, which is consistent with pre-B ALL. The G-banding and fluorescence in situ hybridization analyses indicated Ph(+). After the patient was diagnosed with ALL-L2, induction chemotherapy was performed and imatinib mesylate was thereafter given as the maintenance therapy. Sequencing analysis showed deletion of ABL a2 in the polymerase chain reaction product, which corresponded to a b3a3 fusion transcript. To our knowledge, this is the second report of an aberrant BCR/ABL product lacking ABL exon a2 in childhood ALL.
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PMID:BCR/ABL rearrangement with b3a3 fusion transcript in a case of childhood acute lymphoblastic leukemia. 1921 96

Lymphoblastic lymphoma (LBL) is one of the most frequent occurring pediatric non-Hodgkin lymphomas. In the WHO classification scheme, pediatric LBL is considered to be the same disease entity as pediatric acute lymphoblastic leukemia (ALL). However, it is unclear whether the genetic basis of pediatric LBL development is similar to that of pediatric ALL. We performed genome-wide analyses of copy number aberrations in 12 T-LBL and 7 precursor B-cell LBL pediatric cases using high-resolution SNP-based array CGH. Similar to what previously has been found in T-ALL, T-LBL exhibited recurrent deletions of the CDKN2A locus, occurring in 92% of the cases. Additionally, we detected deletions of RB1 (16%), duplications of MYB (16%), and an amplification of ABL1 in one case. These results show that, similar to T-ALL, the genomic alterations in T-LBL predominantly target genes involved in cell cycle progression. The majority of precursor B-cell LBL was characterized by high-hyperdiploidy (71%), and showed high resemblance with high-hyperdiploid precursor B-cell ALL. Taken together, our data suggest that pediatric LBL and ALL exhibit similar genomic abnormalities within confined immunophenotypic and cytogenetic subgroups, but that the representations of these subgroups differs between the two entities.
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PMID:High-resolution genomic profiling of pediatric lymphoblastic lymphomas reveals subtle differences with pediatric acute lymphoblastic leukemias in the B-lineage. 1938 5

Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosome-positive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases JAK1 (n = 3), JAK2 (n = 16), and JAK3 (n = 1) in 20 (10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P = 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL.
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PMID:JAK mutations in high-risk childhood acute lymphoblastic leukemia. 1947 Apr 74

We report 2 novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age, 16 years), whereas the patients with the deletion were younger (median age, 4 years). The 2 abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Overexpression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 overexpression in lymphoid transformation. In Down syndrome (DS) ALL and 2 non-DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain, suggesting oncogenic cooperation as well as highlighting a link between non-DS ALL and JAK2 mutations.
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PMID:Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia. 1964 Nov 90

Patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) have distinct clinical and biological features. Whereas most DS-ALL cases lack the sentinel cytogenetic lesions that guide risk assignment in childhood ALL, JAK2 mutations and CRLF2 overexpression are highly enriched. To further characterize the unique biology of DS-ALL, we performed genome-wide profiling of 58 DS-ALL and 68 non-DS (NDS) ALL cases by DNA copy number, loss of heterozygosity, gene expression and methylation analyses. We report a novel deletion within the 6p22 histone gene cluster as significantly more frequent in DS-ALL, occurring in 11 DS (22%) and only 2 NDS cases (3.1%) (Fisher's exact P=0.002). Homozygous deletions yielded significantly lower histone expression levels, and were associated with higher methylation levels, distinct spatial localization of methylated promoters and enrichment of highly methylated genes for specific pathways and transcription factor-binding motifs. Gene expression profiling demonstrated heterogeneity of DS-ALL cases overall, with supervised analysis defining a 45-transcript signature associated with CRLF2 overexpression. Further characterization of pathways associated with histone deletions may identify opportunities for novel targeted interventions.
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PMID:Genomic profiling in Down syndrome acute lymphoblastic leukemia identifies histone gene deletions associated with altered methylation profiles. 2217 67

ETV6-RUNX1 gene fusion is usually an early, prenatal event in childhood acute lymphoblastic leukemia (ALL). Transformation results in the generation of a persistent (> 14 years) preleukemic clone, which postnatally converts to ALL after the acquisition of necessary secondary genetic alterations. Many cancer cells show some expression of the erythropoietin receptor (EPOR) gene, although the "functionality" of any EPOR complexes and their relevant signaling pathways in nonerythroid cells has not been validated. EPOR mRNA is selectively and ectopically expressed in ETV6-RUNX1(+) ALL, but the presence of a functional EPOR on the cell surface and its role in leukemogenesis driven by ETV6-RUNX1 remains to be identified. Here, we show that ETV6-RUNX1 directly binds the EPOR promoter and that expression of ETV6-RUNX1 alone in normal pre-B cells is sufficient to activate EPOR transcription. We further reveal that murine and human ETV6-RUNX1(+) cells expressing EPOR mRNA have EPO ligand binding activity that correlates with an increased cell survival through activation of the JAK2-STAT5 pathway and up-regulation of antiapoptotic BCL-XL. These data support the contention that ETV6-RUNX1 directly activates ectopic expression of a functional EPOR and provides cell survival signals that may contribute critically to persistence of covert premalignant clones in children.
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PMID:ETV6-RUNX1 promotes survival of early B lineage progenitor cells via a dysregulated erythropoietin receptor. 2190 Jan 95

A reciprocal translocation between chromosomes 9 and 22 creates oncogenic BCR/ABL fusion in the breakpoint region of the derivative chromosome 22. The aim of this study was to evaluate the importance of atypical fluorescence in situ hybridization (FISH) signal patterns in pediatric and adult acute lymphoblastic leukemia (ALL) cases. We evaluated t(9;22) translocation in 208 cases with ALL (294 tests), including 139 childhood and 69 adult cases by FISH technique using BCR/ABL extra signal (ES) probe. FISH signal patterns observed in pediatric ALL cases were as follows; Major-BCR/ABL (M-BCR/ABL) (1.4%), minor-BCR/ABL (m-BCR/ABL) (3.6%), trisomy 9 (4.3%), trisomy 22 (4.3%), trisomy or tetrasomy of both chromosomes 9 and 22 (2.9%), monosomy 9 (1.4%), monosomy 22 (0.7%), ABL gene amplification (1.4%), derivative chromosome 9 deletion (1.4%), and extra copies of the Philadelphia chromosome (1.4%). FISH signal patterns observed in adult ALL cases were as follows; M-BCR/ABL (5.8%), m-BCR/ABL (11.6%), two different cell clones with major and minor BCR/ABL signal pattern (2.9%), extra copies of Philadelphia chromosome (4.3%), derivative chromosome 9 deletion (1.4%), trisomy 9 (2.9%), tetraploidy (1.4%), monosomy 9 (1.4%), trisomy 22 (1.4%), and coexistence of both trisomy 22 and monosomy 9 (1.4%). Trisomy 9, trisomy 22, and polyploidy of chromosomes 9 and 22 were specific atypical FISH signal patterns for childhood B cell acute lymphoblastic leukemia (B-ALL) patients. However, monosomy 9 and ABL gene amplification were highly specific for childhood T cell acute lymphoblastic leukemia (T-ALL) patients. Our report presents the correlation between atypical FISH signal patterns and clinical findings of a large group of ALL cases.
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PMID:Aberrations of chromosomes 9 and 22 in acute lymphoblastic leukemia cases detected by ES-fluorescence in situ hybridization. 2236 Aug 68


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