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)

The classification of acute leukemia has traditionally been based on a combination of morphology and cytochemical staining data, including myeloperoxidase (MPO) reaction; however, a recent World Health Organization (WHO) classification entails use of cytogenetic and molecular findings in addition to the classic morphological and immunophenotypic analyses. Nevertheless, there have been rare cases in which blastic cells show multilineage phenotypes. These cases may be classified as acute leukemia of ambiguous lineage in the recent WHO classification. We report the case of a 49-year-old man with acute leukemia with multilineage phenotypes. Morphological findings led to a diagnosis of acute myeloid leukemia M2 by the French-American-British classification, but at light microscopy the results of MPO staining were negative for blast cells. In contrast, results of reverse transcription polymerase chain reaction and fluorescence-activated cell sorter analyses were positive for expression of MPO messenger RNA and protein. The blast cells expressed CD4, CD19, CD22, CD33, CD38, CD79a, and HLA-DR and showed rearrangement of the immunoglobulin heavy chain and TCR-3 genes. Results of immunoelectron microscopic analysis of the blast cells were positive for MPO, CD19, CD33, CD34, CD38 and glycophorin A but not for platelet peroxidase. According to these results, the blast cells had at least 4 lineage phenotypes. We concluded that the multiparameter analyses conducted in this case, including immunological and ultrastructural assays, were important in arriving at the appropriate diagnosis of acute leukemia of ambiguous lineage in the new WHO classification.
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PMID:Multilineage involvement of light microscopic myeloperoxidase-negative acute leukemia. 1629 22

Recent data suggest that myeloid neoplasms are organized hierarchically in terms of self-renewal and maturation of early progenitor cells, similar to normal myelopoiesis. In acute myeloid leukemia (AML), the NOD/SCID mouse-repopulating leukemic stem cells usually co-express CD123 with CD34, but lack CD38. So far, however, little is known about expression of other markers and targets on these progenitors. In the present study, expression of target antigens on CD34+/CD38- cells was analysed by multi-color flow cytometry in patients with AML (n = 18), myelodysplastic syndromes (MDS, n = 6), chronic myeloid leukemia (CML, n = 8) and systemic mastocytosis (SM, n = 9). The IL-3Ralpha chain (CD123) was found to be expressed on CD34+/CD38- cells in a majority of the patients in all disease categories. Independent of the type of disease, the vast majority of these stem cells co-expressed aminopeptidase-N (CD13) and CD44 in all patients. By contrast, the CD34+/CD38- progenitor cells expressed variable amounts of the target receptor CD33, c-kit (CD117) and AC133 (CD133). In conclusion, neoplastic stem cells in various myeloid neoplasms appear to express a similar phenotype including target antigens such as CD13, CD33 and CD44. Since many of these targets are not expressed on all stem cells in all patients, the elimination of the entire clone may require combinations of targeted antibodies or use of additional drugs.
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PMID:Detection of molecular targets on the surface of CD34+/CD38-- stem cells in various myeloid malignancies. 1632 50

The interleukin-3 receptor (IL-3R) subunits are overexpressed on acute myeloid leukemia (AML) blasts compared with normal hematopoietic cells and are thus potential targets for novel therapeutic agents. Both fluorescence-activated cell sorter (FACS) analysis and quantitative real-time reverse transcription-polymerase chain reaction (QRT-PCR) were used to quantify expression of the IL-3Ralpha and beta(c) subunits on AML cells. QRT-PCR for both subunits was most predictive of killing of AML colony-forming cells (AML-CFCs) by diphtheria toxin-IL-3 fusion protein (DT(388)IL3). Among 19 patient samples, the relative level of the IL-3Ralpha was higher than the IL-3Rbeta(c) and highest in CD34(+)CD38(-)CD71(-) cells, enriched for candidate leukemia stem cells, compared with cell fractions depleted of such progenitors. Overall, the amount of IL-3Rbeta(c) subunit did not vary among sorted subpopulations. However, expression of both subunits varied by more than 10-fold among different AML samples for all subpopulations studied. The level of IL-3Rbeta(c) expression versus glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (set at 1000) ranged from 0.14 to 13.56 in CD34(+)CD38(-)CD71(-) cells from different samples; this value was correlated (r = .76, P = .05) with the ability of DT(388)IL3 to kill AML progenitors that engraft in beta(2)-microglobin-deficient nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice (n = 7). Thus, quantification of IL-3R subunit expression on AML blasts predicts the effectiveness IL-3R-targeted therapy in killing primitive leukemic progenitors.
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PMID:Expression of interleukin-3 receptor subunits on defined subpopulations of acute myeloid leukemia blasts predicts the cytotoxicity of diphtheria toxin interleukin-3 fusion protein against malignant progenitors that engraft in immunodeficient mice. 1688 9

One has previously characterized two different hematopoietic cell populations (obtained by negative-selection) from normal bone marrow. Population I was enriched for CD34+ Lin- cells, whereas Population II was enriched for CD34+ CD38- Lin- cells. Both populations showed elevated proliferation and expansion potentials in serum-free liquid cultures, supplemented with a combination of eight different cytokines, with the latter displaying more immature features than the former. One has also characterized the chronic myeloid leukemia (CML) counterparts of these two populations and demonstrated functional deficiencies in terms of their growth in culture. In keeping with this line of research, the goal of the present study was to obtain the same two populations (Populations I and II) from acute myeloid leukemia (AML) bone marrow and to characterize their biological behavior under the same culture conditions. The results demonstrated that AML-derived Populations I and II were unable to proliferate in culture conditions that allowed significant proliferation of Populations I and II from normal marrow. Population I from AML also showed a deficient expansion capacity; in contrast, Population II cells were able to expand to a similar extent to the one observed for Population II from normal marrow. Both normal and AML populations were highly sensitive to the inhibitory effects of TNF-alpha; interestingly, whereas in normal fractions TNF-alpha showed a more pronounced inhibitory effect on more mature cells (Population I), this cytokine inhibited proliferation and expansion of AML Populations I and II in a similar degree. It is noteworthy that the functional deficiencies observed in AML cells were even more pronounced than those previously reported for cultures of CML cells. The results reported here may be of relevance considering the interest by several groups in developing methods for the in vitro purging of leukemic cells, as part of protocols for autologous transplantation of hematopoietic cells in leukemic patients.
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PMID:Deficient proliferation and expansion in vitro of two bone marrow cell populations from patients with acute myeloid leukemia in response to hematopoietic cytokines. 1692 72

Tumors contain a fraction of cancer stem cells that maintain the propagation of the disease. The CD34(+)CD38(-) cells, isolated from acute myeloid leukemia (AML), were shown to be enriched leukemic stem cells (LSC). We isolated the CD34(+)CD38(-) cell fraction from AML and compared their gene expression profiles to the CD34(+)CD38(+) cell fraction, using microarrays. We found 409 genes that were at least twofold over- or underexpressed between the two cell populations. These include underexpression of DNA repair, signal transduction and cell cycle genes, consistent with the relative quiescence of stem cells, and chromosomal aberrations and mutations of leukemic cells. Comparison of the LSC expression data to that of normal hematopoietic stem cells (HSC) revealed that 34% of the modulated genes are shared by both LSC and HSC, supporting the suggestion that the LSC originated within the HSC progenitors. We focused on the Notch pathway since Jagged-2, a Notch ligand was found to be overexpressed in the LSC samples. We show that DAPT, an inhibitor of gamma-secretase, a protease that is involved in Jagged and Notch signaling, inhibits LSC growth in colony formation assays. Identification of additional genes that regulate LSC self-renewal may provide new targets for therapy.
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PMID:Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells. 1703 38

This study aimed to identify which subset of CD34+ cells might be the most predictive of early and long-term hematopoietic recovery following autologous peripheral blood stem cell (PBSC) transplantation (PBSCT) in adult acute myeloid leukemia (AML) patients. The relationships between the number of 'mature' subsets of CD34+ cells (CD34+/CD33+, CD34+/CD38+, CD34+/DR+ and CD34+/CD90-) and 'immature' subsets of CD34+ cells (CD34+/CD33-, CD34+/CD38-, CD34+/DR- and CD34+/CD90+) and early and long-term hemoglobin, neutrophil and platelet counts were studied in a homogeneous series (for disease, pre-transplant chemotherapy, mobilization chemotherapy, conditioning regimen) of 26 AML patients after autologous PBSCT. Cell counts were performed before and after cryopreservation, but only after thawing were the cell counts used for correlation with early and long-term engraftment. The number of CD34+/CD38- cells infused correlated with the neutrophil (r = 0.88, p < 0.005) and platelet counts (r = 0.67, p < 0.05) at 12 months after PBSCT. This correlation was better than that for the total CD34+ cell dose at 12 months (r = 0.36, p = 0.09 for neutrophil count and r = 0.48, p = 0.06 for platelets count). The number of CD34+/CD90+ cells was also correlated with the platelet counts at 6 (r = 0.70, p < 0.05) and 12 months (r = 0.80, p = 0.005) after PBSCT. This correlation was better than the total dose of CD34+ cells at 6 (r = 0.31, p = 0.3) and 12 months (r = 0.48, p = 0.06) for the platelet counts. CD34+ subset analysis suggests that for early engraftment the total number of CD34+ cells infused is more strongly correlated than the CD34+ subsets, whereas the CD34+/CD38- and CD34+/CD90+ subsets may be associated with sustained long-term neutrophil and platelet engraftment. These findings may help to predict the repopulating capacity of PBSCs in AML patients after autologous PBSCT, especially when a relatively low number of CD34+ cells is infused.
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PMID:Early and long-term engraftment after autologous peripheral stem cell transplantation in acute myeloid leukemia patients. 1711 22

In order to analyze the clinical characteristics and biological features of acute leukemia in elderly, 104 acute leukemia patients in elderly were retrospectively analyzed and compared with 71 acute leukemia patients below 60 years old. The results showed that: (1) the proportion of AML in the aged group (73%) was higher than that in the young group (54.9%), and the difference was statistically significant (P < 0.05), but AML (M3) was absent in the aged group; (2) the median of bone marrow blast cell in the aged group was significantly lower than that in the young group (P < 0.05); (3) in AML, the frequently of CD14 expression was higher in the aged group (18.8%) than that in the young group (2.6%), while the expression frequencies of CD15 (37.5%), CD117 (62.5%), and CD38 (59.4%) were respectively lower in the aged group than that in the young group which were (69.2%) for CD15, (89.7%) for CD17, and (84.6%) for CD38 respectively, and the difference was also statistically significant (P < 0.05). (4) CD19 was most frequently expressed in ALL of the aged group and the positive rate was 100%; (5) there was no significant difference in expression of special lineage antigens and overlapping lineage antigens between the aged group and the young group (P > 0.05); (6) the expression frequency of unfavorable karyotypes in the aged group was higher than that in the young group, and the difference was statistically very significant (P < 0.01); (7) the complete remission rate (CR rate) in the aged group was 42.9%, 2-year survival rate in the aged group was 5.4%, and treatment-related mortality rate in the aged group was 26.8%, while the CR rate in the young group was 76.6%, the difference was statistically significant (P < 0.05). It is concluded that the expression frequency of CD14 associated with unfavorable prognosis is higher in the aged group than that in the young group, while the expression frequency of CD15 associated with favorable prognosis is lower in the aged group than that in the young group. The expression frequency of unfavorable karyotypes in the aged group is higher than that in the young group. The CR rate of acute leukemia in elderly is low, thus the patients in elderly often have unfavorable prognosis.
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PMID:[Clinical characteristics and immunophenotype of aged patients with acute leukemia]. 1720 98

Activating mutation of FLT3 by internal tandem duplications (ITDs) in the juxtamembrane region is the most common molecular aberration found in acute myeloid leukaemia (AML). In this study, a lentiviral vector containing two promoters achieved consistent and efficient co-expression of FLT3/ITD and GFP in transduced human CD34(+) haematopoietic stem/progenitor cells (HSPCs). When cultured in medium containing stem cell factor, thrombopoietin and FLT3 ligand (FL), FLT3/ITD-transduced cells demonstrated enhanced self-renewal and survival potential, unaffected by the withdrawal of FL. These cells retained a CD34(+)CD38(-/dim) immunophenotype, typical of HSPCs. Compared to cells transduced with a vector expressing GFP alone, FLT3/ITD-transduced HSPCs had a higher fraction of cells in active cell cycle. FLT3/ITD-transduced HSPCs were more sensitive to the induction of cytotoxicity by CEP-701, a selective FLT3 inhibitor, indicating a rapid 'addiction' to signalling through this oncogenic pathway. The FLT3/ITD-transduced HSPCs showed increased expression of Pim-1, c-Myc and Cyclin D3 (CCND3), each of which may contribute to the altered genetic programme instituted by FLT3/ITD signalling. Taken together, these results indicate that FLT3/ITD mutations may contribute to leukaemic transformation of normal HSPCs by prolonging survival, promoting proliferation and partially blocking differentiation. CEP-701 may act as a potent therapeutic agent for AML stem cells harbouring FLT3/ITD mutations.
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PMID:FLT3/ITD expression increases expansion, survival and entry into cell cycle of human haematopoietic stem/progenitor cells. 1735 72

Acute myeloid leukemia (AML) is generally regarded as a stem cell disease. In CD34-positive AML, the leukemic stem cell has been recognized as CD38 negative. This CD34+CD38- population survives chemotherapy and is most probable the cause of minimal residual disease (MRD). The outgrowth of MRD causes relapse and MRD can therefore serve as a prognostic marker. The key role of leukemogenic CD34+CD38- cells led us to investigate whether they can be detected under MRD conditions. Various markers were identified to be aberrantly expressed on the CD34+CD38- population in AML and high-risk MDS samples at diagnosis, including C-type lectin-like molecule-1 and several lineage markers/marker-combinations. Fluorescent in situ hybridization analysis revealed that marker-positive cells were indeed of malignant origin. The markers were neither expressed on normal CD34+CD38- cells in steady-state bone marrow (BM) nor in BM after chemotherapy. We found that these markers were indeed expressed in part of the patients on malignant CD34+CD38- cells in complete remission, indicating the presence of malignant CD34+CD38- cells. Thus, by identifying residual malignant CD34+CD38- cells after chemotherapy, MRD detection at the stem cell level turned out to be possible. This might facilitate characterization of these chemotherapy-resistant leukemogenic cells, thereby being of help to identify new targets for therapy.
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PMID:Aberrant marker expression patterns on the CD34+CD38- stem cell compartment in acute myeloid leukemia allows to distinguish the malignant from the normal stem cell compartment both at diagnosis and in remission. 1752 25

Permanent cure of acute myeloid leukemia (AML) by chemotherapy alone remains elusive for most patients because of the inability to effectively eradicate leukemic stem cells (LSCs), the self-renewing component of the leukemia. To develop therapies that effectively target LSC, one potential strategy is to identify cell surface markers that can distinguish LSC from normal hematopoietic stem cells (HSCs). In this study, we employ a signal sequence trap strategy to isolate cell surface molecules expressed on human AML-LSC and find that CD96, which is a member of the Ig gene superfamily, is a promising candidate as an LSC-specific antigen. FACS analysis demonstrates that CD96 is expressed on the majority of CD34(+)CD38(-) AML cells in many cases (74.0 +/- 25.3% in 19 of 29 cases), whereas only a few (4.9 +/- 1.6%) cells in the normal HSC-enriched population (Lin(-)CD34(+)CD38(-)CD90(+)) expressed CD96 weakly. To examine whether CD96(+) AML cells are enriched for LSC activity, we separated AML cells into CD96(+) and CD96(-) fractions and transplanted them into irradiated newborn Rag2(-/-) gamma(c)(-/-) mice. In four of five samples, only CD96(+) cells showed significant levels of engraftment in bone marrow of the recipient mice. These results demonstrate that CD96 is a cell surface marker present on many AML-LSC and may serve as an LSC-specific therapeutic target.
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PMID:CD96 is a leukemic stem cell-specific marker in human acute myeloid leukemia. 1757 27


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