Gene/Protein Disease Symptom Drug Enzyme Compound
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Mutations of the CCAAT/enhancer binding protein alpha (CEBPA) gene have been associated with a favorable outcome in patients with acute myeloid leukemia (AML), but mainly in those with a normal karyotype. Here, we analyzed the impact of associated cytogenetic abnormalities or bad-prognosis fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in 53 patients with CEBPA(+) de novo AML treated in the Acute Leukemia French Association trials. We found that only those with a normal karyotype and no FLT3-ITD displayed the expected favorable outcome. In this context, relapse-free, disease-free, and overall survival were significantly longer than in corresponding patients without the CEBPA mutation (P = .035, .016, and .047, respectively). This was not observed in the context of an abnormal karyotype or associated FLT3-ITD. Furthermore, after adjustment on age, trial, and mutation type, these features were independently predictive of shorter overall survival in the subset of patients with CEBPA(+) AML (multivariate hazard ratio = 2.7; 95% confidence interval, 1.08-6.7; and 2.9; 95% confidence interval, 1.01-8.2; with P = .034 and .05, for abnormal karyotype and FLT3-ITD, respectively).
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PMID:The favorable impact of CEBPA mutations in patients with acute myeloid leukemia is only observed in the absence of associated cytogenetic abnormalities and FLT3 internal duplication. 1928 55

Mouse spleens contain three major dendritic cell (DC) populations: plasmacytoid DC, conventional CD8(+)CD24(+) DC (CD8(+) DC), and conventional CD8(-)CD24(-) DC (CD8(-) DC). We have previously shown that CD8(+) DC are the major cross-presenting subtype in vivo and are the main inducers of antiviral cytotoxic T lymphocyte responses. Here we show that after depletion of CD8(+) DC, the only DC capable of viral Ag presentation was a small subset that expresses CD24 but not CD8. This CD8(-)CD24(+) DC population is greatly expanded in mice treated with the DC growth factor FMS-like tyrosine kinase 3 ligand. The CD8(-)CD24(+) DC represent an immediate precursor of CD8(+) DC, as demonstrated by their expression pattern of characteristic markers of CD8(+) DC, their capacity to cross-present in vitro, and their conversion into CD8(+) DC upon adoptive transfer into recipient mice. Accordingly, the lifespan of transferred CD8(-)CD24(+) DC in vivo was greatly enhanced as compared with terminally differentiated CD8(+) DC. Moreover, in a vaccination protocol, CD8(-)CD24(+) DC induced stronger T cell responses and accelerated viral clearance of HSV-1 compared with CD8(+) DC. Our results demonstrate that the ability to cross-present first appears in an immediate precursor population of CD8(+) DC that does not yet express CD8. The enhanced capacity of CD8(-)CD24(+) DC to induce immune responses upon adoptive transfer makes them an attractive novel tool for DC-based immunotherapies.
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PMID:Characterization of an immediate splenic precursor of CD8+ dendritic cells capable of inducing antiviral T cell responses. 1929 18

FMS-like tyrosine kinase 3 (FLT3) inhibitors have shown activity in the treatment of acute myelogenous leukemia (AML). Secondary mutations in target kinases can cause clinical resistance to therapeutic kinase inhibition. We have previously shown that sensitivity toward tyrosine kinase inhibitors varies between different activating FLT3 mutations. We therefore intended to determine whether different FLT3 inhibitors would produce distinct profiles of secondary, FLT3 resistance mutations. Using a cell-based screening approach, we generated FLT3-internal tandem duplication (ITD)-expressing cell lines resistant to the FLT3 inhibitors SU5614, PKC412, and sorafenib. Interestingly, the profile of resistance mutations emerging with SU5614 was limited to exchanges in the second part of the kinase domain (TK2) with exchanges of D835 predominating. In contrast, PKC412 exclusively produced mutations within tyrosine kinase domain 1 (TK1) at position N676. A mutation at N676 recently has been reported in a case of PKC412-resistant AML. TK1 mutations exhibited a differential response to SU5614, sorafenib, and sunitinib but strongly impaired response to PKC412. TK2 exchanges identified with SU5614 were sensitive to PKC412, sunitinib, or sorafenib, with the exception of Y842D, which caused a strong resistance to sorafenib. Of note, sorafenib also produced a highly distinct profile of resistance mutations with no overlap to SU5614 or PKC412, including F691L in TK1 and exchanges at position Y842 of TK2. Thus, different FLT3 kinase inhibitors generate distinct, nonoverlapping resistance profiles. This is in contrast to Bcr-Abl kinase inhibitors such as imatinib, nilotinib, and dasatinib, which display overlapping resistance profiles. Therefore, combinations of FLT3 inhibitors may be useful to prevent FLT3 resistance mutations in the setting of FLT3-ITD-positive AML.
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PMID:FMS-like tyrosine kinase 3-internal tandem duplication tyrosine kinase inhibitors display a nonoverlapping profile of resistance mutations in vitro. 1931 74

Acute myeloid leukemia (AML) is a heterogeneous disease with outcomes dependent upon several factors, including patient age, karyotype, mutational status, and comorbid conditions. For younger patients, approximately 60% to 80% achieve complete remission with standard therapy involving cytarabine and an anthracycline. However, only 20% to 30% have long-term disease-free survival. For adults older than 60 years of age, only 40% to 55% achieve a complete remission, with dismal long-term survival rates. Unfortunately, the median age at diagnosis for AML is 70 years. Significant advances in our understanding of the molecular biology of AML have led to newer therapies that specifically target molecular abnormalities. Examples of such therapies include the immunoconjugate gemtuzumab ozogamicin, FMS-like tyrosine kinase 3 inhibitors, farnesyl transferase inhibitors, histone deacetylase inhibitors, DNA hypomethylating agents, multidrug-resistance inhibitors, BCL-2 inhibitors, antiangiogenesis agents, and various nucleoside analogs. This review summarizes the standard treatments for AML and discusses the role of novel therapies.
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PMID:Acute myelogenous leukemia. 1946 67

Acute myeloid leukemia (AML) is a disease with a poor prognosis. It has been demonstrated that AML cells express vascular endothelial growth factor (VEGF) as well as Flt-1 and KDR, resulting in an autocrine pathway for cell survival. PTK787/ZK 222584 is a new oral antiangiogenic molecule that inhibits tyrosine kinase activity of all known VEGF receptors. The present study aimed to investigate the therapeutic efficacy of combining PTK787/ZK 222584 with a chemotherapeutic agent, such as Idarubicin, for treatment of AML. We have analyzed in four AML cell lines and seven AML patient samples, cell proliferation, apoptosis, angiogenesis. and activation of several related intracellular pathways after treatment with PTK787/ZK 222584 alone or combined with Idarubicin. PTK787/ZK 222584 decreased VEGF levels and VEGF receptor phosphorylation in the AML cells showing Fms-like tyrosine kinase 3/internal tandem duplication mutation (Flt3/ITD). Both drugs, given separately, inhibited cell proliferation and promoted apoptosis. Moreover, combined treatment promoted more apoptosis and inhibition of cell proliferation than each compound administered separately in all AML cells. In conclusion, PTK787/ZK 222584 combined with Idarubicin achieved a better therapeutic efficacy than chemotherapy alone in AML cells, especially in those with Flt3/ITD, in which the combination further prevented activation of the angiogenic process.
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PMID:Additive effect of PTK787/ZK 222584, a potent inhibitor of VEGFR phosphorylation, with Idarubicin in the treatment of acute myeloid leukemia. 1946 70

Hematopoiesis is highly regulated through cytokine-induced stimulation of multiple signal transduction pathways in order to mediate appropriate differentiation and proliferation of specific progenitor populations. Ligand-induced stimulation of the FMS-like tyrosine kinase 3 (FLT3) leads to activation of multiple downstream effector pathways resulting in differentiation and proliferation of specific progenitor cell populations. Genomic alterations of the FLT3 gene, including FLT3 internal tandem duplication (FLT3/ITD) and FLT3 activation loop mutation (FLT3/ALM) lead to autonomous receptor activation, dysregulation of FLT3 signal transduction pathways, contribute to myeloid pathogenesis, and have been linked to response to therapy and clinical outcome. Exploring the mechanisms by which these FLT3 alterations lead to dysregulated proliferation should provide a better understanding of the molecular pathogenesis of acute myeloid leukemia (AML) and may provide insights into potential therapeutic interventions. FLT3 inhibitors are under evaluation for their efficacy in AML patients with FLT3 mutations.
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PMID:Structural and functional alterations of FLT3 in acute myeloid leukemia. 1954 78

This study was aimed to investigate the status of c-KIT, Fms-like tyrosine kinase 3 (FLT3) and Janus kinase 2 (JAK2) mutations in acute myeloid leukemia (AML) patients with t (8; 21) and to analyze their relation to clinical feature and prognosis. PCR, AS-PCR, restriction and sequencing methods were used respectively to detect the FLT3, JAK 2 and c-KIT mutations in 8 cases of de novo AML with t (8; 21) and 6 cases of relapsed AML with t (8; 21). The results showed that the c-KIT mutation was found in 2 cases out of 14 AML patients with t (8; 21) (14.3%), among them 1 case had c-KIT D816V mutation, the other had c-KIT D816Y mutation. The FLT3-ITD mutation was detect in 1 out of 14 patients (7.1%), but JAK2 mutation could not be detected in all 14 cases. In conclusion, tyrosine kinase mutation relates to AML with t (8; 21), patients with tyrosine kinase mutation may have higher relapse, extramedullary infiltration and poor prognosis. The screening c-KIT, FLT3 mutations may play an important role in evaluating prognosis and guiding treatment of t (8; 21) AML.
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PMID:[Tyrosine kinase mutation and acute myeloid leukemia with T (8; 21)]. 1969 18

This study was aimed to investigate the frequency of FMS-like tyrosine kinase 3 (FLT3) mutations including internal tandem duplication (ITD) mutation of juxtamembrane region and point mutation of the second tyrosine kinase domain (TKD) in acute myeloid leukemia (AML) patients and its clinical significance. The ITD mutation in FLT3 exon 14, 15 of bone marrow mononuclear cells was detected by genomic DNA-PCR, the TKD point mutation in FLT3 exon 20 was detected by genomic DNA-PCR combined with restriction endonuclease digest. The results indicated that among 131 newly diagnosed AML patients, 21 patients (16.0%) showed FLT3-ITD positive, 3 patients (2.3%) showed FLT3-TKD positive. None was found harboring both mutations. The WBC and bone marrow blast counts in FLT3-ITD positive patients seemed both higher than those in patients with wild-type FLT3 (FLT3-wt), but there was significant difference only in WBC count (p<0.05). The complete remission (CR) rate in FLT3-ITD positive patients was 47.6%, which was significantly lower than that in FLT3-wt patients (88.1%, p<0.05). There was no statistical difference in CR rate between FLT3-ITD positive and negative patients in 20 cases of M3; the CR rate in FLT3-ITD positive patients with non M(3) was 37.5 (6/16) which was obviously lower than that in FLT3-wt patients with non M3 (90.6%, 48/53) (p<0.05). 3 FLT3-ITD positive patients with CR relapsed after CR for 14 (2-20) months with relapse rate 50% (3/6) which was higher than that in FLT3-wt patients (29.2%, 14/48). It is concluded that FLT3 mutation is common in AML patients, while FLT3-ITD mutation is more frequent than FLT3-TKD mutation. The AML patients with FLT3-ITD mutation have a poor prognosis, while FLT3-TKD point mutation does not significantly influences prognosis of the patients. Therefore early detection of FLT3 mutation may be important for targeting therapy and evaluating clinical prognosis of AML patients.
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PMID:[FMS-like tyrosine kinase 3 gene mutations in acute myeloid leukemia]. 1984 Apr 37

Mutation of the FMS-like tyrosine kinase 3 (FLT3) gene in Indian population remains unclear till date. Here, we found FLT3-ITD mutations in 19.1%, FLT3-Asp835 mutations in 4.7%, and dual mutations in 4.2%, accounting for overall mutation in 28% of acute myeloid leukemia (AML) patients. FLT3 mutation was more prevalent in APL than non-APL patients (32.2% vs 26.3%), adults tend to show higher incidence than children (30.6% vs 18.2%, p = .1), and were significantly associated with normal karyotype, high WBCs, with no specific distribution in FAB subtypes. Notably, FLT3 mutation was present in 50% of patients with NPM1-Mt, when compared to only 22.6% of patients with NPM1-wt (p < .001). Sequence analyses of internal tandem duplications (ITDs) revealed that duplications were mostly restricted to JM domain (3 to 165 nucleotides). Interestingly, 92.3% cases showed duplication of at least one amino acid (AA) within the stretch Y589 to K602 that includes the two SH2-binding motifs. Analysis of frequency of single AA in the duplicated region revealed that E598 was the most frequently duplicated single AA in 72%, followed by R595 (69.2%), and Y599 (66.7%). Finally, three types of point mutations were identified, including D835Y, D835H, and D835A.
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PMID:Analysis of FLT3-ITD and FLT3-Asp835 mutations in de novo acute myeloid leukemia: evaluation of incidence, distribution pattern, correlation with cytogenetics and characterization of internal tandem duplication from Indian population. 1999 25

Retroviral expression of leukemogenic oncogenes in the murine hematopoietic system is essential but not sufficient to induce acute leukemia. Proviral integration-mediated elevated expression of the meningioma 1 (MN1) oncogene suggested MN1 acting as cooperating event in mixed-lineage leukemia 1 (MLL) and eleven nineteen leukemia (ENL)-induced murine leukemia. Indeed, co-expression of MN1 with MLL-ENL enhanced transformation in vivo, and resulted in a significantly reduced latency for induction of an aggressive acute leukemia when compared with MN1 or MLL-ENL alone. In addition, co-expression of MN1 increased the granulocyte macrophage progenitor cell population with leukemia-initiating properties as shown in secondary transplantation experiments. Gene expression profiling experiments identified putative downstream MN1 targets, of which FMS-like tyrosine kinase 3 (FLT3) and CD34 were upregulated in both MN1-overexpressing murine leukemias and in pediatric acute leukemias with high MN1 levels. Interestingly, small interfering RNA (siRNA)-mediated MN1 knockdown resulted in cell cycle arrest and impaired clonogenic growth of human leukemia cell lines with high MN1 levels. Our work shows for the first time that high MN1 levels are important for the growth of leukemic cells, and that increased MN1 expression can synergize with MLL-ENL and probably other transforming fusion genes in leukemia induction through a distinct gene expression program that is able to expand the leukemia-initiating cell population.
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PMID:Functional characterization of high levels of meningioma 1 as collaborating oncogene in acute leukemia. 2007 57


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