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)

In the past few decades, the results of treatment for childhood acute lymphoblastic leukemia (ALL) have achieved about 80% long-term disease-free survival (DFS). Although the complete remission (CR) rate of adult ALL has also improved from 70 to 90%, 5-year overall survival (OS) remains only about 30% because of the high incidence of relapse. Especially, the disease with Philadelphia chromosome-positive (Ph+) ALL has been considered to have a poor prognosis. Recently, the selective inhibitor of BCR-ABL kinase, imatinib, showed significant efficacy in the treatment of Ph+ALL, and imatinib-combined chemotherapy for Ph+ALL is expected to improve the prognosis of this disease. At the same time, resistance to imatinib, resulting in relapse, is also reported. Once the patient relapses, subsequent cure becomes unlikely. The current available treatment to prevent recurrence of the disease is allogeneic hematopoietic transplantation (HST), if there is an HLA-matched donor. In Ph-negative (Ph-) ALL, young adults have superior outcomes with a 5-year OS of 81% when treated in pediatric clinical trials. HST may not always be necessary for this group of patients. For patients without donor or older than 50, novel biologic or targeted therapies are warranted, and early detection of minimal residual disease may also change strategies and improve the outcome of this disease.
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PMID:[Acute lymphoblastic leukemia (ALL)]. 1807 17

We examined the prognostic impact of cytogenetics on the outcome of 200 acute lymphoblastic leukemia (ALL) patients 15 to 65 years of age enrolled in Southwest Oncology Group (SWOG)-9400 study. Evaluable cytogenetics or fluorescence in situ hybridization studies were available in 140 (70%) patients. Four karyotype categories (normal [n = 31, 22%], t(9;22)/BCR/ABL1 [n = 36, 26%], other unfavorable [-7, +8, or 11q23 rearrangement, n = 19, 13%], and miscellaneous [n = 54, 39%]) and the biologically and clinically relevant ALL ploidy subgroups were prospectively defined. Overall survival (OS) decreased significantly with increasing age (P = .009) and varied with karyotype category (P < .001). OS was worst for t(9;22)/BCR/ABL1 followed by other unfavorable karyotypes, with hazard ratios (HR) of 3.45 (95% confidence interval [CI], 1.88-6.31) and 2.14 (95% CI, 1.04-4.04), respectively, compared with normal diploid group. OS of the miscellaneous group was similar to that of the normal diploid group (HR = 0.82; 95% CI, 0.44-1.53). Relapse-free survival (RFS) was not significantly associated with age (P = .30) but was heterogeneous among karyotype categories (P < .001) primarily because of poor RFS in t(9;22)/BCR/ABL1 (HR = 3.49; 95% CI, 1.80-6.75) compared with the normal diploid group. After accounting for the variation among karyotype groups, age was not a significant prognostic factor for OS or RFS, highlighting cytogenetics as the most important prognostic factor in adult ALL. This trial was registered at www.ClinicalTrials.gov as #NCT00002665.
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PMID:Impact of cytogenetics on the outcome of adult acute lymphoblastic leukemia: results of Southwest Oncology Group 9400 study. 1815 92

In acute lymphoblastic leukemia, besides age and white cell count at diagnosis, the cytogenetic abnormalities t(9;22)/BCR-ABL and t(4;11)/MLL-AF4 are important prognostic markers and are often included in the treatment stratification of patients with adult acute lymphoblastic leukemia. Deletions in 9p are seen in about 9% of cases of adult acute lymphoblastic leukemia, but their prognostic impact has been controversial. Cytogenetic data from 381 patients diagnosed with B-precursor acute lymphoblastic leukemia were reviewed. Chromosomal analysis was successful in 240 cases. Of these cases, 18 (8%) had abnormalities in 9p and they were compared with patients with normal karyotypes and patients with t(9;22)/BCR-ABL. Patients with abnormalities of chromosome 9 showed significantly shorter overall survival compared with patients with normal karyotypes. In fact, overall survival was similar to that in the poor prognosis t(9;22)/BCR-ABL-positive group. Our data suggest that chromosomal abnormalities involving 9p may have a significant negative impact on survival in adult B-precursor acute lymphoblastic leukemia.
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PMID:An investigation into whether deletions in 9p reflect prognosis in adult precursor B-cell acute lymphoblastic leukemia: a multi-center study of 381 patients. 1872 22

Treatment results in adult acute lymphoblastic leukemia (ALL) have improved considerably in the past decade, with an increase of complete remission rates to 85% to 90% and overall survival rates to 40% to 50%. Superior chemotherapy and supportive care, the integration of stem cell transplantation (SCT) into frontline therapy, and optimized risk stratification were important developments. Even more impressive is the success of targeted therapies in subgroups of ALL. In the formerly most unfavorable subgroup, Philadelphia chromosome (Ph)/BCR-ABL-positive ALL, survival now ranges from 40% to 50% after incorporating imatinib in combination chemotherapy. In mature B-ALL, survival rates increased above 80% with the combination of short intensive chemotherapy and rituximab. The prerequisite for comprehensive therapy is standardized and rapid diagnosis and classification as the basis for treatment stratification. Historically, the major aim of original risk stratification was to identify patients with a poor prognosis who would benefit from treatment intensification with SCT; currently stratification has become more complex. Subgroup-specific approaches include age-adapted therapy, subgroup-adjusted therapy, targeted therapy, and individualized therapy based on the presence of minimal residual disease (MRD).
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PMID:Treatment of adult acute lymphoblastic leukemia. 1910 Mar 69

MLL translocations in adult B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) are largely restricted to the immature CD10(-) immunophenotypes. MLL-AF4 is known to be the most frequent fusion transcript, but the exact frequencies of MLL aberrations in CD10(-) adult BCP-ALL are unknown. We present a genetic characterization of 184 BCR-ABL(-) CD10(-) adult ALL cases (156 cyIg(-), 28 cyIg(+)) diagnosed between 2001 and 2007 at the central diagnostic laboratory of the GMALL study group. Patient samples were investigated by RT-PCR for MLL-AF4, MLL-ENL, and MLL-AF9 and by long-distance inverse polymerase chain reaction, thus also allowing the identification of unknown MLL fusion partners at the genomic level. MLL-AF4 was detected in 101 (54.9%) and MLL-ENL in 11 (6.0%) cases. In addition, rare MLL fusion genes were found: 2 MLL-TET1 cases, not previously reported in ALL, 1 MLL-AF9, 1 MLL-PTD, a novel MLL-ACTN4, and an MLL-11q23 fusion. Chromosomal breakpoints were determined in all 118 positive cases, revealing 2 major breakpoint cluster regions in the MLL gene. Characteristic features of MLL(+) patients were significantly lower CD10 expression, expression of the NG2 antigen, a higher white blood count at diagnosis, and female sex. Proposals are made for diagnostic assessment.
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PMID:The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group. 1914 82

Between 2000 and 2006, 85 adult BCR-ABL negative acute lymphoblastic leukaemia (ALL) patients between 18 and 60 years of age were treated using a modified paediatric regimen, which included high doses of asparaginase delivered weekly for 30 weeks during intensification. The complete response rate with induction therapy was 89%, and decreased with increasing age, mainly due to higher induction mortality. All post-induction treatments were delivered on an outpatient basis. The most common complications during intensification were infections (47%), osteonecrosis (32%), venous thromboembolism (23%) and neuropathy (22%). At a median follow-up of 4 years, the 5-year overall survival (OS) and relapse-free survival (RFS) were 63% and 71%, respectively. Significant adverse predictors for OS were age >35 years, high white blood cell count, MLL rearrangement, allogeneic stem cell transplantation in first complete remission and <80% of the planned asparaginase dose delivered during intensification. Patients aged < or = 35 years had a 3 year OS of 83%, as compared to 52% for patients aged >35 years. We conclude that the administration of this paediatric regimen is feasible and has considerable activity in adult ALL, particularly in younger patients. Effective delivery of asparaginase dosing appears to be important in achieving an optimal antileukaemic effect.
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PMID:Treatment of adults with BCR-ABL negative acute lymphoblastic leukaemia with a modified paediatric regimen. 1943 71

B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre-B cell receptor-dependent stages. The Philadelphia chromosome-positive (Ph(+)) subtype of ALL accounts for 25-30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre-B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph(+) ALL cells. Pre-B cell receptor-mediated cell cycle arrest in Ph(+) ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre-B cell receptor signaling pathway, even if expression of the pre-B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre-B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph(+) ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre-B cell receptor-mediated tumor suppression.
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PMID:Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function. 1962 Jun 27

The interaction between Wilms tumor gene 1 (WT1) and the promoter region of the multidrug resistance-1 (MDR1) gene has been previously reported but the clinical significance of the coexpression of WT1 and MDR1 in acute lymphoblastic leukemia (ALL) is still largely unknown. In this study, the expression levels of WT1 and MDR1 mRNA in 57 adult ALL patients were simultaneously detected using multiplex fluorescence real-time quantitative polymerase chain reaction. The expression levels of WT1 and MDR1 in bone marrow samples of adult ALL patients were significantly higher than those in the normal samples (P<0.001), and in addition, the expression levels of WT1 and MDR1 mRNA were highly correlated (r(s)=0.404, P=0.002). According to the expression levels of these two genes, the patients in this study were subdivided into the following three groups: low-WT1/low-MDR1 (n=16), high-WT1 or high-MDR1 (n=24), high-WT1/high-MDR1 (n=17). There was no significant difference in response to induction therapy among these three cohorts (P=0.217). The overall first year relapse rate was 53.2% (25 out of 47 ALL patients). High-WT1/high-MDR1 mRNA expression was strongly associated with BCR-ABL expression and a higher tendency to be T-cell ALL type. In addition, high-WT1/high-MDR1 have a significantly higher relapse rate (P=0.048) and shorter disease free survival (P=0.016). Our data suggests that high-WT1/high-MDR1 levels of mRNA expression may be associated with relatively poorer outcomes in patients with ALL. Therefore, the expression of WT1 and MDR1 may provide useful information for clinical decision.
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PMID:Simultaneous detection of MDR1 and WT1 gene expression to predict the prognosis of adult acute lymphoblastic leukemia. 2042 67

Although three-way Philadelphia (Ph) variant translocation has been uncommonly (3~8%) reported in chronic myeloid leukemia (CML), it has been even more rarely described in acute leukemias (ALs). When we reviewed the Mitelman database and the literature, we found about 595 three-way Ph variant cases; among these, only 39 three-way Ph variant translocations in AL were documented. Here, we report a novel three-way Ph variant case of t(8;9;22) in adult acute lymphoblastic leukemia (ALL). Based on bone marrow morphology, chromosome fluorescent in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and flow cytometrry, this patient was diagnosed with B lymphoblastic leukemia/lymphoma associated with both t(8;9;22) (q21;q34;q11.2) and BCR/ABL1 rearrangement (e1a2 type). Because of the rarity of reported AL patients with three-way Ph variant, further studies on their prognosis and treatment response to imatinib mesylate are necessary.
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PMID:A novel three-way Ph variant t(8;9;22) in adult acute lymphoblastic leukemia. 2132 59

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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