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)

We describe a 35-year-old woman with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) who received allogeneic sibling donor peripheral blood stem cell transplantation (PBSCT) and entered a second complete remission. Upon detection of BCR-ABL transcripts after PBSCT, the patient received imatinib, leading to molecular remission. Following the failure of donor leukocyte infusions, she underwent reduced-intensity unrelated cord blood transplantation (RI-UCBT), and has continued durable molecular remission for more than 30 months without substantial graft-versus-host disease. Because of a lack of adverse effects of imatinib on transplantation outcome, a treatment strategy consisting of molecular monitoring-guided initiation of imatinib followed by RI-UCBT may be promising in the management of Ph+ ALL after allogeneic SCT.
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PMID:Successful treatment of minimal residual disease-positive Philadelphia chromosome-positive acute lymphoblastic leukemia with imatinib followed by reduced-intensity unrelated cord blood transplantation after allogeneic peripheral blood stem cell transplantation. 1692 41

It is generally believed that shutting down the kinase activity of BCR-ABL by imatinib will completely inhibit its functions, leading to inactivation of its downstream signaling pathways and cure of the disease. Imatinib is highly effective at treating human Philadelphia chromosome-positive (Ph(+)) chronic myeloid leukemia (CML) in chronic phase but not Ph(+) B cell acute lymphoblastic leukemia (B-ALL) and CML blast crisis. We find that SRC kinases activated by BCR-ABL remain fully active in imatinib-treated mouse leukemic cells, suggesting that imatinib does not inactivate all BCR-ABL-activated signaling pathways. This SRC pathway is essential for leukemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis. Inhibition of both SRC and BCR-ABL kinase activities by dasatinib affords complete B-ALL remission. However, curing B-ALL and CML mice requires killing leukemic stem cells insensitive to both imatinib and dasatinib. Besides BCR-ABL and SRC kinases, stem cell pathways must be targeted for curative therapy of Ph(+) leukemia.
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PMID:Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice. 1707 47

While imatinib is highly effective therapy, with improving prospects over time for sustained remission and potential to severely limit or eliminate disease progression and transformation, a minority of patients either fail or respond suboptimally to imatinib; as well, disease eradication may not be possible with imatinib. Distinct patterns of resistance have evolved with the use of imatinib, and Abl kinase mutations, which alter imatinib binding or favor kinase conformations inaccessible to imatinib, are a common finding associated with clinical resistance. Dasatinib and nilotinib, alternate Abl kinase inhibitors, restore hematologic and cytogenetic remission in the majority of patients with primary failure or acquired resistance in chronic phase disease; in advanced disease and Philadelphia chromosome (Ph)(+) ALL, responses are more limited and relapse is common. Future studies with these agents will focus on further optimizing imatinib response, reduction of minimal residual disease, and prevention of resistance. Still newer inhibitors active against T315I mutant BCR-ABL may overcome primary and secondary resistance to dasatinib and nilotinib.
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PMID:Defining and managing imatinib resistance. 1712 64

We carried out sequential molecular monitoring of different markers on two BCR-ABL positive ALL patients receiving a standard dose induction regimen, which was followed by a maintenance therapy that alternated imatinib and chemotherapy administration. Molecular study was performed at diagnosis, at the end of the induction phase, and then every three months during maintenance therapy. Each marrow sample underwent BCR-ABL analysis (p210 and p190 expression by RT-PCR and Real-time PCR) and monoclonal JH rearrangement analysis, while WT1 gene expression was detected by Real-time PCR. At diagnosis we detected high WT1 expression associated with the presence of both BCR-ABL transcripts and monoclonal JH rearrangement in both patients. Hematological remission, as well as a molecular status characterized by undetectable BCR-ABL expression, normal levels of WT1 expression, and persistence of monoclonal JH rearrangement, were achieved by both patients post-therapy. Follow up of patient 1 showed a progressive increase in WT-1 and in p-190 transcript, which was followed by cytogenetic and hematological relapse. We observed a progressive increase in the p210 transcript without a concomitant increase in WT-1 levels in patient 2. JH rearrangement was detected in all the samples analyzed. The molecular results may indicate the persistence of JH rearranged clonal cells with undetectable BCR-ABL. From a clinical point of view, our preliminary experience suggests that simultaneous analysis of BCR-ABL, JH and WT-1 expression may improve the study of MRD in Ph+ ALL.
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PMID:Monitoring molecular response by BCR-ABL, JH and WT-1 in Ph+ all treated with imatinib containing regimen: preliminary report of two cases. 1716 71

Session 4 of the 2005 Society of Hematopathology/European Association for Haematopathology Workshop focused on case presentations of precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (pre-T ALL/LBL) and acute biphenotypic leukemia. Pre-T ALL represents approximately 15% of childhood and 25% of adult ALL cases. Pre-T LBL comprises 85% to 90% of LBL and frequently manifests as a mediastinal mass. Gene expression studies have shown distinct subtypes of LYL1+, HOX11+, TAL1+, and MLL+ pre-T ALL/LBL. HOX11 overexpression may correlate with a good prognosis in adult pre-T ALL. ABL gene amplification and NOTCH1 gene mutations in subsets of pre-T ALL/LBL suggest patients may benefit from therapy with tyrosine kinase and gamma-secretase inhibitors, respectively. Acute biphenotypic leukemias are characterized by a single population of blasts that express myeloid, T- or B-lineage antigens in various combinations and account for fewer than 4% of all acute leukemias. The blasts have a high incidence of chromosome abnormalities. An accurate diagnosis of pre-T ALL/LBL and acute biphenotypic leukemia requires a multiparametric approach, including examination of morphologic features, immunophenotype, clinical characteristics, and cytogenetic and molecular findings.
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PMID:Precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma and acute biphenotypic leukemias. 1736 28

Acquired imatinib resistance in advanced Philadelphia-positive acute lymphoblastic leukemia (Ph(+) ALL) has been associated with mutations in the kinase domain (KD) of BCR-ABL. We examined the prevalence of KD mutations in newly diagnosed and imatinib-naive Ph(+) ALL patients and assessed their clinical relevance in the setting of uniform frontline therapy with imatinib in combination with chemotherapy. Patients enrolled in the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) trial ADE10 for newly diagnosed elderly Ph(+) ALL were retrospectively examined for the presence of BCR-ABL KD mutations by denaturing high-performance liquid chromatography (D-HPLC), cDNA sequencing, and allele-specific polymerase chain reaction (PCR). A KD mutation was detected in a minor subpopulation of leukemic cells in 40% of newly diagnosed and imatinib-naive patients. At relapse, the dominant cell clone harbored an identical mutation in 90% of cases, the overall prevalence of mutations at relapse was 80%. P-loop mutations predominated and were not associated with an inferior hematologic or molecular remission rate or shorter remission duration compared with unmutated BCR-ABL. BCR-ABL mutations conferring high-level imatinib resistance are present in a substantial proportion of patients with de novo Ph(+) ALL and eventually give rise to relapse. This provides a rationale for the frontline use of kinase inhibitors active against these BCR-ABL mutants.
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PMID:Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). 1740 7

The study was aimed to investigate the relation between the expression level of TEL-AML1 (translocation ETS leukemia-acute myeloid leukemia 1) fusion gene and clinical characteristics as well as early response to treatment in children with ALL (acute lymphoblastic leukemia). With real-time quantitative polymerase chain reaction (RQ-PCR), the expression level of TEL-AML1 at diagnosis and MRD (minimal residual disease) at the end of induction of remission were detected in 35 children with ALL, including 20 SR (standard risk) and 15 IR (intermediate risk) patients. The expression level of TEL-AML1 and clinical characteristics at diagnosis were compared between MRD negative and MRD positive patients. The relation between TEL-AML1 expression levels at diagnosis, MRD level and clinical characteristics as well as early response to treatment were also explored. The results indicated that the expression levels of TEL-AML1 at diagnosis were 1.63 x 10(4) copies/10(4) copies ABL (median). At the end of induction of remission, 16 patients (10 SR and 6 IR patients) did not achieve molecular remission, whose MRD levels were 0.84 - 282.93 copies/10(4) copies ABL. No relation was found between expression levels of TEL-AML1 at diagnosis and clinical characteristics as well as MRD level. There was a significant relation between MRD level and blast count in peripheral blood (PB) at day 8 after prednisone trial induction. Significant relations between MRD level and presenting leukocyte count, blast percentage in PB were also found in the patients with presenting leukocyte count < 25 x 10(9)/L. TEL-AML1 expression level at diagnosis of MRD negative patients was lower than that of MRD positive ones. It is concluded that therapy after induction of remission is of importance by the fact that 45.71% children with TEL-AML1(+) ALL did not achieve molecular remission at the end of induction of remission. The effectiveness of prednisone trial predicts the MRD level. In addition, presenting leukocyte count, blast percentage in PB and TEL-AML1 expression level at diagnosis may have an effect on MRD level to some extent.
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PMID:[Relation between TEL-AML1 expression level and clinical characteristics as well as early response to treatment in children with acute lymphoblastic leukemia]. 1760 58

The BCR-ABL-fusion gene is critical for the development of chronic myeloid leukemia (CML) and BCR-ABL positive acute lymphatic leukemia (Ph+ ALL). Blocking BCR-ABL by the ABL tyrosine kinase inhibitor imatinib mesylate (IM, Gleevec) is clinically highly efficient. Treatment response is unfortunately compromised by the emergence of IM resistance, which is regularly seen in accelerated and blastic phase of CML (CML-AP/BP) and in Ph+ ALL. BCR-ABL kinase domain mutations are then considered the causative mechanism of IM resistance, because 50-60% of the IM resistant patients harbour such mutations. In contrast, IM resistance arises very rarely in patients that are treated with IM in early chronic phase of CML. This implies that BCR-ABL independent factors such as the cellular context of BCR-ABL expression and stage of disease decisively control the evolution of IM resistance. In line with this, novel Abl-kinase inhibitors such as dasatinib (DA) or nilotinib (NI) - although capable of inhibiting most of the BCR/-BL kinase mutants - still often fail to overcome resistance and do mostly not induce durable cytogenetic responses in IM resistant CML-AP/BC and Ph+ ALL patients. On the basis of available evidence it is proposed here that alternative genetic aberrations, which synergize with BCR-ABL to enable leukemic self-renewal are of causal importance for the evolution of clinical kinase inhibitor resistance. Kinase mutations may in turn reflect clonal variants of cells that emerge on the basis of an already existing IM resistant and self-renewing leukemic cell population. This model has clinical implications as it implies that even highly potent Abl-kinase inhibition can not target the genetic basis of IM resistance and will also not resolve the problem of Abl-kinase inhibitor resistance.
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PMID:Roots of imatinib resistance: a question of self-renewal? 1768 77

RT-PCR is the method of choice for detecting BCR-ABL in CML and ALL. The three predominant mRNA transcripts found are e1a2 (in ALL), e13a2, and e14a2 (in CML and ALL). However, a number of "atypical"BCR-ABL transcripts (e1a3, e13a3, e14a3, e19a2, e6a2, e8a2, etc.) resulting from chromosomal breakpoints outside ABL intron 1 or BCR intron 1, 13 or 14, respectively, have been reported. These atypical transcripts may escape detection when using methods that are optimized to detect just the typical ones. We present here a novel, fast, and reliable multiplex PCR for improved detection of typical and atypical BCR-ABL transcripts.
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PMID:A multiplex PCR for improved detection of typical and atypical BCR-ABL fusion transcripts. 1792 51

The BCR-ABL kinase inhibitor imatinib has shown significant efficacy in chronic myeloid leukemia (CML) and is the standard front-line therapy for patients in chronic phase. However, a substantial number of patients are either primarily refractory or acquire resistance to imatinib. While a number of mechanisms are known to confer resistance to imatinib, increasing evidence has demonstrated a role for BCR-ABL-independent pathways. The Src-family kinases (SFKs) are one such pathway and have been implicated in imatinib resistance. Additionally, these kinases are key to the progression of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The dual SFK/BCR-ABL inhibitor dasatinib is now clinically available and has markedly greater potency compared with imatinib against native BCR-ABL and the majority of imatinib-resistant BCR-ABL mutants. Therefore, this agent, as well as other dual SFK/BCR-ABL inhibitors under development, could provide added therapeutic advantages by overcoming both BCR-ABL-dependent (i.e. BCR-ABL mutations) and -independent forms of imatinib resistance and delaying transition to advanced phase disease. In this review, we discuss the preclinical and clinical evidence demonstrating the involvement of SFKs in imatinib resistance and the progression of CML and Ph+ ALL, as well as the potential role of dual SFK/BCR-ABL inhibition in the management of these diseases.
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PMID:Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia. 1820 7


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