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

Point mutations of D835/I836 of the FLT3 gene have been reported in adult acute myeloid leukemia (AML), but not in pediatric AML or acute lymphoblastic leukemia (ALL). FLT3-D835/I836 mutations were found in 6 (5.4%) of 112 children with ALL older than 1 year and in 8 (16.0%) of 50 infants with ALL. Missense mutations were found in 11 patients, 3-base pair deletions in 2 patients, and a deletion/insertion in 1 patient. Remarkably, FLT3-D835/I836 mutations were found in 8 (18.2%) of 44 infants with ALL with MLL rearrangements and in 4 (21.5%) of 19 patients with hyperdiploid ALL, but they were not found in any patients older than 1 year who had TEL-AML1 (n = 11), E2APBX1 (n = 4), or BCR-ABL (n = 6) fusion genes. Although infant ALL patients with mutations had poorer prognoses than did those without mutations, pediatric ALL patients with mutations who were older than 1 year had good prognoses. We also found FLT3-D835 mutations in 2 of 11 leukemic cell lines with MLL rearrangements. FLT3 was highly phosphorylated in these cell lines with FLT3-D835 mutations, leading to constitutive activation of downstream targets such as signal transducer and activator of transcription 5 (STAT5) without FLT3 ligand stimulation. These results suggested that FLT3-D835/I836 mutations are one of the second genetic events in infant ALL with MLL rearrangements or pediatric ALL with hyperdiploidy.
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PMID:FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. 1450 97

The KG-1 cell line, established from bone marrow cells of a patient with erythroleukemia evolving to acute myelogenous leukemia, and its less differentiated variant, KG-1a, are widely used in research worldwide. However, to our knowledge, neither cell line was studied by use of molecular-cytogenetic techniques such as spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH). Our G-banding, SKY, and FISH analyses revealed a complex karyotype with a pseudodiploid modal chromosome number in both the KG-1 and KG-1a cell lines. The lines shared several identical structural aberrations, including der(4)t(4;8), del(7q), der(8)t(8;12), idic(8)(p11), der(17)t(5;17), and der(20)t(12;20), but also differed with regard to other chromosome rearrangements. In contrast to KG-1, the KG-1a line lost one of the two copies of idic(8)(p11) present in KG-1 cells and gained a der(8;22)(q24;q13), an i(11)(q10), and a der(19)t(14;19)(q13;q13.4). Notably, we have shown that the KG-1 cells harbor a partial hexasomy of the long arm of chromosome 8, which may explain in part the previously reported significantly higher rate of formation of the AML1-ETO fusion gene in KG-1 cells subjected to high-dose gamma irradiation compared with the rates of formation of the BCR-ABL or the DEK-CAN fusion gene. Our detailed description of chromosome rearrangements in KG-1 and KG-1a will be useful for the cytogenetic authentication of the lines, and provide clues as to the regions of the genome that could be studied further to explain the differences in phenotypic properties between KG-1 and KG-1a cells.
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PMID:Molecular cytogenetic characterization of the KG-1 and KG-1a acute myeloid leukemia cell lines by use of spectral karyotyping and fluorescence in situ hybridization. 1450 99

The transcription factor C/EBPalpha plays a critical role in the process of granulocytic differentiation. Recently, mutations that abrogated transcriptional activation of C/EBPalpha were detected in acute myeloid leukemia patient samples. Moreover, the progression of chronic myelogenous leukemia (CML) to blast crisis in patients was correlated with down-modulation of C/EBPalpha. The KCL22 cell line, derived from BCR-ABL+ CML in blast crisis, expressed wild-type C/EBPepsilon protein but not a functional C/EBPalpha, -beta, and -gamma. Restoration of C/EBPalpha expression in KCL22 cells triggered a profound proliferative arrest, a block in the G2/M phase of the cell cycle and a gradual increase in apoptosis. Within 3 days of inducing expression of C/EBPalpha, a remarkable neutrophilic differentiation of the KCL22 blast cells occurred as shown by morphologic changes, induction of expression of CD11b, primary, secondary, and tertiary granule proteins, and granulocyte colony-stimulating factor receptor. Using high density oligonucleotide microarrays, the gene expression profile of KCL22 cells stably transfected with C/EBPalpha was compared with that of empty vector, and we identified genes not previously known to be regulated by C/EBPalpha. These included the up-regulation of those genes important for regulation of hematopoietic stem cell homing, granulocytic differentiation, and cell cycle, whereas down-regulation occurred for genes coding for signaling molecules and transcription factors that are implicated in regulation of proliferation and differentiation of hematopoietic cells. Our study showed that restoration of C/EBPalpha expression in BCR-ABL+ leukemic cells in blast crisis is sufficient for rapid neutrophil differentiation suggesting a potential therapeutic role for ectopic transfer of C/EBPalpha in acute phase of CML.
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PMID:Restoration of C/EBPalpha expression in a BCR-ABL+ cell line induces terminal granulocytic differentiation. 1451 14

Cancer is also an epigenetic disease. The main epigenetic modification in humans is DNA methylation. Transformed cells undergo a dramatic change in their DNA methylation patterns: certain CpG islands located in the promoter regions of tumor-suppressor genes become hypermethylated and the contiguous gene rests silenced and this phenomenon occurs in an overall genomic environment of DNA hypomethylation. The profile of CpG island hypermethylation in hematologic malignancies is an epigenetic signature unique for each subtype of leukemia or lymphoma. Although the most widely studied genes are the cell-cycle inhibitors p15INK4b and p16INK4a (specially in AML and ALL), the list of methylation-repressed genes in these neoplasms is expanding very rapidly, including MGMT, RARB2, CRBP1, SOCS-1, CDH1, DAPK1, and others. A necessary cross-talk between genetic alterations and DNA methylation exists: certain chromosomal translocations may induce hypermethylation, such as the PML-RARa, or attract methylation, such as BCR-ABL, but DNA hypomethylation can be the culprit behind the genesis of certain abnormal recombination events. From a translational standpoint, hypermethylation can be used as a marker of recurrent disease or progression, for example, in MDS, or response to chemotherapy, such as MGMT methylation in B-cell non-Hodgkin's lymphoma. Furthermore, promising studies using DNA demethylating agents and histone deacetylase inhibitors are underway to awake these dormant tumor-suppressor genes for a better treatment of the patient with a hematologic malignancy.
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PMID:Profiling aberrant DNA methylation in hematologic neoplasms: a view from the tip of the iceberg. 1458 79

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the BCR-ABL fusion protein in CML, and was superior to IFN-alpha plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in BCR-ABL-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular BCR-ABL protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-TRANS-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-alpha (PML/RARalpha) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.
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PMID:Apoptosis induced by molecular targeting therapy in hematological malignancies. 1464 49

After allogeneic stem cell transplantation (SCT), we evaluated the use of the Wilms' tumor gene (WT1) as a minimal residual disease (MRD) marker in 32 patients (28 chronic myeloid leukemia, three acute lymphoblastic leukemia and one acute myeloid leukemia). All patients expressed BCR-ABL and the kinetics of WT1 were compared with those of BCR-ABL using real-time quantitative PCR. WT1 expression was seen in the peripheral blood (PB) of healthy controls with a median expression level of 7 x 10(-5) (WT1/ABL ratio). The corresponding values for BCR-ABL-negative and BCR-ABL-positive patient samples were 1 x 10(-4) and 1.6 x 10(-4), respectively. Kinetic studies in individual patients showed that WT1 and BCR-ABL levels usually did not copy each other. In four out of six patients who relapsed, an increase in WT1 from the background level (10(-4)) was observed only at the time of or after relapse, and in two patients increasing WT1 levels were observed before the relapse. In addition, the WT1 values found at the time of relapse were only two logs higher than the background level, indicating a sensitivity of 10(-2). In conclusion, there is a constitutive low expression of WT1 in normal hematopoietic cells. The sensitivity and ability of WT1 to predict a relapse were poor in this study.
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PMID:Poor correlation of kinetics between BCR-ABL and WT1 transcript levels after allogeneic stem cell transplantation. 1525 61

We conducted a retrospective study to define the significance of Philadelphia chromosome (Ph) in myelodysplastic syndrome and acute leukemia in the adults at this institution and the literature was reviewed. One hundred forty-eight cases of t(9;22)(q34;q11) were identified for the period September 1993 through August 2001. The presentation of 124 cases (84%) was that of typical CML in chronic phase. Nineteen cases (13%) presented as de novo ALL, two cases (1%) presented as de novo AML and three cases (2%) presented as myelodysplastic syndrome (MDS). The estimated incidences of t(9;22)(q34;q11) in ALL and AML are 21 and 0.6%, respectively. Ph+ AMLs are increasingly being reported with either M-BCR or m-BCR gene rearrangements, similar to those found with Ph+ ALL lending support to the notion that Ph+ AMLs are distinct entities and not merely blastic phases of undiagnosed CML. This is further supported by the existence of Ph+ MDS cases.
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PMID:Philadelphia chromosome positive myelodysplastic syndrome and acute myeloid leukemia-retrospective study and review of literature. 1512 Sep 28

Philadelphia-chromosome (Ph)-positive acute myeloid leukemia (AML) is rare and prognosis is poor with a median survival of six to seven months only. We report on a patient with Ph-positive AML (FAB M2, major BCR/ABL1 mRNA transcript, b2a2), who is in sustained complete cytogenetic and molecular remission for 15 months. Cytarabine-based chemotherapy was discontinued after two courses due to infectious complications. Since the b2a2 transcript was still detectable, imatinib was started with quantitative RT-PCR monitoring. This result is promising and worth further evaluation to establish the role of imatinib in patients with Ph-positive AML.
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PMID:Complete molecular remission in a patient with Philadelphia-chromosome positive acute myeloid leukemia after conventional therapy and imatinib. 1513 44

The formation of a leukemogenic fusion product in hematopoietic malignancies is commonly achieved by chromosomal translocation. Alternate and cytogenetically undetectable mechanisms of fusion transcript generation have been documented for BCR-AB1, AML1-ETO, PML-RARA, NPM/ALK, and MLL-MLLT2 (AF4). Here, we report the investigation of a cryptic rearrangement leading to MLL-MLLT3 transcript formation. Cytogenetic analysis of peripheral blood from a 50-year-old acute myeloid leukemia patient yielded a karyotype of 47,XY,+8,del(11)(q21q23) in all metaphase cells examined. Metaphase fluorescence in situ hybridization analysis using the MLL probe at 11q23 revealed that the 5' portion of the MLL gene was inserted into chromosome 9 at band p22, whereas the 3' region of the MLL gene remained on chromosome 11. Whole-chromosome paint analysis confirmed the cryptic transfer of chromosome 11 material to 9p22. With this information, the karyotype was reassigned as 47,XY,+8,der(9)ins(9;11)(p22;q23q23),del(11)(q21q23). RT-PCR was used to show that the cryptic rearrangement in this patient led to the fusion of the MLL and MLLT3 transcripts on the der(9). The presence of the MLL-MLLT3 transcript is consistent with the clinical findings in this patient.
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PMID:Cryptic insertion of MLL gene into 9p22 leads to MLL-MLLT3 (AF9) fusion in a case of acute myelogenous leukemia. 1518 59

Internal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL-positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.
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PMID:Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. 1524 81


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