Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

While acute myeloid leukemia (AML) is significantly less common than acute lymphoblastic leukemia (ALL) in childhood, it is significantly more deadly with only half as many children likely to be cured with standard therapy. In addition, the typical treatment for AML is among the most toxic of treatments for pediatric cancer; it includes intensive multiagent chemotherapy and, often, hematopoietic stem cell transplantation. Given the poor prognosis of pediatric AML and the significant toxicity of standard AML therapy, novel therapies are needed. Improved understanding of the molecular and cellular biology of leukemia has facilitated the development of molecularly targeted therapies. In this article, we review progress to date with agents that are showing promise in the treatment of pediatric AML including targeted immunoconjugates, inhibitors of signaling molecules (e.g. FMS-like tyrosine kinase 3 [FLT3], farnesyltransferase, and mammalian target of rapamycin [mTOR]), agents that target epigenetic regulation of gene expression (DNA methyltransferase inhibitors and histone deacetylase inhibitors), and proteasome inhibitors. For the specific agents in each of these classes, we summarize the published preclinical data and the clinical trials that have been completed, are in progress, or are being planned for children with AML. Finally, we discuss potential challenges to the success of molecularly targeted therapy including demonstrating adequate targeting of leukemia stem cells, developing synergistic and tolerable combinations of agents, and designing adequately powered clinical trials to test efficacy in molecularly defined subsets of patients.
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PMID:Molecularly targeted therapies for pediatric acute myeloid leukemia: progress to date. 1834 18

Activating mutations of the FMS-like tyrosine kinase 3 gene (FLT3) occur in approximately one-third of patients with acute myeloid leukaemia (AML) and predict for a poor outcome. Heat shock protein 90 (Hsp90) is a molecular chaperone that is frequently used by cancer cells to stabilise mutant oncoproteins. Mutant FLT3 is chaperoned by Hsp90 in primary AML blasts whereas unmutated FLT3 is not, making Hsp90 inhibitors potentially useful therapeutically. The present study showed that inhibition of Hsp90 by 17-allylamino-17-demethoxygeldanamycin (17-AAG) was cytotoxic to primary AML cells expressing mutant FLT3. Inhibition of Hsp90 results in altered downstream signalling effects in primary AML cells with disruption of Janus kinase-signal transducer and activator of transcription (JAK-STAT), mitogen-activated protein kinase and phosphatidylinositol 3/AKT signalling pathways. Co-treatment of blasts with 17-AAG and cytarabine resulted in a synergistic or additive effect in approximately 50% of AML cases tested. Our results confirm that Hsp90 is a valid molecular target in the therapy of AML. Inhibition of Hsp90 in parallel with conventional AML therapies may have particular benefit in those patients with the poor prognostic FLT3 mutant disease.
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PMID:Heat shock protein 90 inhibition is cytotoxic to primary AML cells expressing mutant FLT3 and results in altered downstream signalling. 1837 9

This study explored the effect of MS-275, a novel histone deacetylase inhibitor (HDACI), against a variety of human leukemia cells with defined genetic alterations. MS-275 profoundly induced growth arrest of acute myelogenous leukemia (AML) MOLM13 and biphenotypic leukemia MV4-11 cells, which possess internal tandem duplication mutation in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD), with IC50s less than 1 microM, as measured by 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay on day two of culture. Exposure of these cells to MS-275 decreased levels of total, as well as, phosphorylated forms of FLT3, resulting in inactivation of its downstream signal pathways, including Akt, ERK, and STAT5. Further studies found that MS-275 induced acetylation of heat shock protein 90 (HSP90) in conjunction with ubiquitination of FLT3, leading to degradation of FLT3 proteins in these cells. This was blunted by treatment with the proteasome inhibitor bortezomib, confirming that FLT was degraded via ubiquitin/proteasome pathway. Moreover, we found that further inhibition of MEK/ERK signaling potentiated the action of MS-275 in leukemia cells. Taken together, MS-275 may be useful for treatment of individuals with leukemia possessing activating mutation of FLT3 gene.
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PMID:MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. 1839 2

FMS-like tyrosine kinase 3 (FLT3) is a type III receptor tyrosine kinase that is expressed on the surface of hematopoietic stem cells and plays an important role in normal hematopoiesis. FLT3 is mutated in approximately one-third of cases of acute myeloid leukemia (AML) with normal karyotype. The mutations are most commonly internal tandem duplications found in the juxtamembrane domain of the FLT3 receptor. There are also cases of point mutations within the tyrosine kinase domain. The presence of a FLT3 mutation confers a poorer prognosis in disease-free survival and overall survival. Patients with an FLT3 mutation have poorer outcomes even with a concomitant nucleophosmin1 (NMP1) mutation, which is normally a good prognostic factor. These observations raise the question about how best to treat patients with AML who have FLT3 mutations. There are some retrospective data that allogeneic stem cell transplantation should be offered to patients with FLT3 mutations who have achieved a first remission, but prospective trials are lacking. There are a number of FLT3 inhibitors that are in various stages of clinical testing. It is hoped that this new class of drugs will be combined with traditional cytotoxic therapies to treat AML and improve outcomes in this difficult-to-treat patient population.
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PMID:Implications of FLT3 mutations in the therapy of acute myeloid leukemia. 1847 98

We compared the antitumor activities of the multitargeted tyrosine kinase inhibitors imatinib, sorafenib, and sunitinib to determine which inhibitor is best suited to be used for the treatment of acute myelogenous leukemia (AML). In nine human AML cell lines, sorafenib and sunitinib were more potent inhibitors of cellular proliferation than imatinib (IC50, 0.27 to >40, 0.002-9.1, and 0.007-13 micromol/L for imatinib, sorafenib, and sunitinib, respectively). Sorafenib and sunitinib were potent inhibitors of cells with fms-like tyrosine kinase 3 internal tandem duplication (IC50, 2 and 7 nmol/L) and c-KIT N822K mutations (IC50, 23 and 40 nmol/L). In four cell lines (MV4-11, Kasumi-1, KG-1, and U937) that spanned a range of drug sensitivities, sorafenib and sunitinib had similar activity in apoptosis and cell cycle assays, except that sunitinib did not promote apoptosis in U937 cells. Both drugs inhibited mitogen-activated protein kinase signaling but had no effect on AKT signaling in most of the cell lines tested. Sorafenib was substantially more bound than sunitinib in human plasma (unbound fraction, 0.59% versus 8.4%) and cell culture medium (unbound fraction, 1.3% versus 39%), indicating that sorafenib was more potent than sunitinib and that unbound sorafenib concentrations with activity against most AML cell lines are achievable in vivo. There was more intracellular accumulation of sorafenib than of sunitinib and imatinib in AML cells. Between 1 and 10 micromol/L, sorafenib inhibited the proliferation of six of nine primary AML blast samples by > or =50%. Our results highlight the pharmacologic features of sorafenib that may provide it an advantage in the treatment of AML.
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PMID:Comparison of antitumor effects of multitargeted tyrosine kinase inhibitors in acute myelogenous leukemia. 1848

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and risk for evolving to acute leukemia. Some molecular abnormalities related to acute myeloid leukemia (AML) transformation have been reported, such as FLT3 (FMS-like tyrosine kinase 3) mutations. FLT3, a member of the class 3 receptor tyrosine kinase family, mediates stem cell proliferation and differentiation, and its mutations, internal tandem duplication (ITD) and Asp835, have been reported in rare MDS patients. We studied FLT3 ITD, prospectively, in 50 MDS patients at diagnosis, at 6 and 12 months follow-up, and at any other time-point if AML transformation was detected. FLT3 ITD was not observed at diagnosis, but during follow-up the mutation was present in 2 of 50 patients (4%). Of these, one case exhibited FLT3 ITD at the end of the 6 months of follow-up in approximately 8% of bone marrow cells; this case evolved into AML at 8 months, at which time FLT3 ITD was present in approximately 85% of bone marrow cells. The other case exhibited FLT3 ITD in 68% of bone marrow cells at 7 months, precisely at the time of AML transformation. Although rare in MDS, FLT3 ITD is associated with a high probability of evolution to AML.
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PMID:FLT3 internal tandem duplication during myelodysplastic syndrome follow-up: a marker of transformation to acute myeloid leukemia. 1850 25

Immunotherapy is now considered in acute myelogenous leukemia (AML). A dendritic cell (DC) phenotype can be induced in primary human AML cells by in vitro culture in the presence of various cytokine combinations. The aim was to investigate whether this phenotypic alteration is associated with altered chemokine release. AML cells were cultured according to four protocols that have been characterized in detail for AML-DC induction: (1) granulocyte-macrophage colony-stimulating factor (GM-CSF) + interleukin-4 (IL-4) days 1-14 and tumor necrosis factor-alpha (TNF-alpha) for days 6-14, (2) GM-CSF + IL-4 + TNF-alpha + FMS-like tyrosine kinase 3-ligand (Fl3-L) for 8 days, (3) GM-CSF + IL-4 + TNF-alpha + Flt3-L + stem cell factor (SCF) + transforming growth factor-beta1 (TGF-beta1) for 8 days, and (4) 25 Gy gamma-irradiation combined with culture in the presence of GM-CSF + SCF + IL-3 for 4 days. Significantly increased AML-DC release of CCL17 and CCL22 was observed for protocols 1, 2, and 3, whereas effects on CCL2-5, CXCL8, and CXCL10 differed in all protocols. Neutralization studies using a transwell migration assay demonstrated the increased level of CCL17 and CCL22 release was important for AML-DC chemotaxis of normal T cells. Induction of a dendritic AML cell phenotype is associated with an altered chemokine release profile. Detailed characterization of chemokine release should be included in future studies of AML-DC vaccination.
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PMID:In vitro induction of a dendritic cell phenotype in primary human acute myelogenous leukemia (AML) blasts alters the chemokine release profile and increases the levels of T cell chemotactic CCL17 and CCL22. 1854 60

Acute myeloid leukemia (AML) is the most common childhood malignancy. AML has therapeutically been difficult to treat. In 2001, the World Health Organization (WHO), in conjunction with the Society for Hematopathology and the European Association of Hematopathology, published a new classification for myeloid neoplasms. A number of chromosomal abnormalities are used to predict outcome and stratify therapeutic risk groups in children with AML. Recently, alterations in receptor tyrosine kinases, tyrosine phosphatases and in oncogenes such as RAS have been implicated in the pathogenesis of AML. This article aims to review the recent development in diagnosis, treatment and monitoring of AML. Better understanding of the molecular pathogenesis of AML has led to the development of target-specific therapies. Some of the new classes of drugs include monoclonal antibody directed against the CD33 antigen, farnesyltransferase inhibitors (FTI), and FMSlike tyrosine kinase 3 (FLT3) inhibitors. The role of allogenic SCT, particularly whether it should be done during first CR or reserved for second remission, remains the most controversial issue in pediatric AML. There is a need of collaboration with international pediatric cooperative oncology groups and definitive clinical trials in order to establish use of these newer molecules in pediatric populations.
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PMID:Recent advances in management of acute myeloid leukemia (AML). 1876 95

Because protein function regulates the phenotypic characteristics of cancer, a functional proteomic classification system could provide important information for pathogenesis and prognosis. With the goal of ultimately developing a proteomic-based classification of acute myeloid leukemia (AML), we assayed leukemia-enriched cells from 256 newly diagnosed AML patients, for 51 total and phosphoproteins from apoptosis, cell-cycle, and signal-transduction pathways, using reverse-phase protein arrays. Expression in matched blood and marrow samples were similar for 44 proteins; another 7 had small fold changes (8%-55%), suggesting that functional proteomics of leukemia-enriched cells in the marrow and periphery are similar. Protein expression patterns were independent of clinical characteristics. However, 24 proteins were significantly different between French-American-British subtypes, defining distinct signatures for each. Expression signatures for AML with cytogenetic abnormalities involving -5 or -7 were similar suggesting mechanistic commonalities. Distinct expression patterns for FMS-like tyrosine kinase 3-internal tandem duplication were also identified. Principal component analysis defined 7 protein signature groups, with prognostic information distinct from cytogenetics that correlated with remission attainment, relapse, and overall survival. In conclusion, protein expression profiling patterns in AML correlate with known morphologic features, cytogenetics, and outcome. Confirmation in independent studies may also provide pathophysiologic insights facilitating triage of patients to emerging targeted therapies.
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PMID:Functional proteomic profiling of AML predicts response and survival. 1884 Jul 13

Certain leukemias have a high relapse risk even after allo-SCT, and GVHD prophylaxis with calcineurin inhibitors (CNIs) may interfere with a possible GVL effect. Therefore, we replaced CYA by sirolimus in patients with high relapse risk. In contrast to CNIs, sirolimus promotes the generation of regulatory T-cells and has potent antineoplastic activity. Sirolimus has been used in combination with CNI for GVHD prophylaxis in hematopoietic SCT. However, no CNI-free prophylactic regimen with sirolimus has been evaluated so far. Within the FLAMSA-RIC protocol, 15 patients received GVHD prophylaxis with sirolimus and mycophenolate mofetil (MMF). The underlying diagnoses were relapsed or refractory T-ALL (n=3), AML with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) or mixed-lineage leukemia-partial tandem duplication (MLL-PTD; n=10; 5 with refractory disease) and CML in refractory myeloid blast crisis (n=2). All evaluable patients (n=14) were engrafted. Grades II-IV acute GVHD occurred in 21% and chronic GVHD in 30% of patients. Non-relapse mortality rate was 14%. No thrombotic microangiopathy or sinusoidal obstruction syndrome was observed. Three patients with FLT3-ITD+ AML relapsed after a median of 112 days. At a median follow-up of 10 months after transplantation, 10 patients are alive and in complete remission. In conclusion, sirolimus-based GVHD prophylactic regimens deserve further investigation.
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PMID:Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study. 1901 60


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