Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To identify residual candidate normal progenitor/stem cell populations in childhood B-cell precursor acute lymphoblastic leukaemia (ALL), expression of AC133 and CD117 was analysed on the leukaemic cell clone and on immature B-lineage-negative CD34+CD19- bone marrow cells. 10/25 patients (40%) had no detectable expression of AC133 within the leukaemic cell clone. 24/26 patients (92%) lacked expression of CD117 on the leukaemic blast cell population. In contrast, a distinct AC133-positive cell population was found in 8/8 children with AC133-negative ALL and a CD117-positive cell population could be identified in 12/12 children with CD117-negative ALL, within the CD34+CD19- progenitor/stem cell compartment. These observations provide further evidence that in B-cell precursor ALL, unlike in acute myelogenous leukaemia, it may be possible to distinguish residual normal progenitor/stem cells from the leukaemic cell clone.
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PMID:Expression of AC133 and CD117 on candidate normal stem cell populations in childhood B-cell precursor acute lymphoblastic leukaemia. 1058 62

The identification of immunophenotypic markers with restricted expression has long been a critical issue in diagnostic and therapeutic advances for acute leukemias. We previously developed a monoclonal antibody against a new thymocyte surface antigen, JL1, and showed that JL1 is expressed in the majority of acute leukemia cases. In this study, using multiparameter flow cytometric analyses, we found that JL1 was uniquely expressed in subpopulations of normal bone marrow (BM) cells, implying the association of JL1 with the differentiation and maturation process. Although CD34(+) CD10(+) lymphoid precursors and some of maturing myeloid cells express JL1, neither CD34(+) CD38(-/lo) nor CD34(+) AC133(+) noncommitted pluripotent stem cells do. As for the myeloid precursors, CD34(+) CD33(+) cells do not express JL1. During lymphopoiesis, JL1 on the earliest lymphoid precursors disappear in the CD20(+) sIgM(+) stage of B-cell development or after CD1a down-regulation in thymocytes. Despite the highly restricted expression of JL1 in normal BM cells, most of the leukemias express JL1 irrespective of their immunophenotypes. These results indicate that JL1 is not only a novel differentiation antigen of hematopoietic cells, but also a leukemia-associated antigen. Therefore, we suggest that JL1 be a candidate molecule in acute leukemia for the diagnosis and immunotherapy that spares the normal BM stem cells.
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PMID:Expression of leukemia-associated antigen, JL1, in bone marrow and thymus. 1129 May 65

AC133 is a novel 5-transmembrane antigen present on a CD34((bright)) subset of human hematopoietic stem cells (HSCs) and it is also expressed on the subset of CD34 positive (CD34(+)) leukemias. But the clinical significance of AC133 expression on leukemic blasts is not yet known. We investigated the expression of AC133 antigen on blast cells of acute leukemia. Forty-one cases of acute leukemia were examined for expression of AC133, CD34, and other antigens using multicolor flow-cytometry. Samples were considered positive if at least 20% of the cells specifically stained with monoclonal antibodies (MoAbs) revealed a higher fluorescence intensity compared to cells of corresponding negative control samples (=20% cut-off level). 14/36 (38.9%) acute myelogenous leukemia (AML) samples and 6/20 (30%) acute lymphoblastic leukemia (ALL) samples were positive for AC133, the difference was not significant. All AC133 positive (AC133(+)) leukemias expressed CD34, whereas 13 of 33 CD34(+) leukemias were negative for AC133, and AC133(+)/CD34(-) leukemia was not found. Expression rates of CD31, CD62L, CD62E, CD105 and CD144 were significantly higher in AC133(+) leukemia compared to those of AC133(-) leukemia (P=0.045, P<0.001, P<0.001, P<0.001, P=0.003, respectively), but bcl-2, CXCR-1, CXCR4, VLA-4, CD106 expression rates were not significantly different between AC133(+) and AC133(-) leukemias. None of the clinical prognostic markers such as age, hemogram, lactate dehydrogenase, and chromosomal aberration were significantly different between AC133(+) and AC133(-) leukemias. CR rates of AC133(+) AML and AC133(-) AML were not significantly different, although there was a trend toward higher CR rates in AC133(-) AML (18/22[81.8%] AC133(-) AML versus 9/14[64.3%] AC133(+) AML), but the 1-year relapse rate of AC133(+) AML was significantly higher than that of AC133(-) AML (8/9 (88.9%) versus 7/19 (36.8%), P=0.016). Median disease-free survival (DFS) times of AC133(+) and AC133(-) AML were significantly different (11 and 18 months, respectively, P=0.006), although overall survival (OS) times were not significantly different (AC133(+) 15 months versus AC133(-) 20 months, respectively, P=0.06). Similar results regarding clinical outcomes were found when AC133(+)/CD34(+) and AC133(-)/CD34(+) were analyzed separately, but the difference did not attain statistical significance. In ALL, 9/11 (81.8%) AC133(-) and 2/4 (50%) AC133(+) cases achieved CR, but the difference was not significant. Four of 11 AC133(-) ALL (36.4%) and 2 of 3 AC133(+) ALL (66.7%) relapsed within 1 year. In survival analysis, median DFS time and OS time of the AC133(+) group were 7 and 18 months, respectively, and these were not significantly different from those of the AC133(-) group (median DFS 15, OS 22 months, respectively). Our results demonstrate that AC133 expression in AML blasts is associated with poor clinical outcomes in terms of higher early relapse and shorter disease-free survival, suggesting that the AC133 antigen might provide the prognostic stratification of acute leukemia. However, to verify the effect of AC133 expression on the therapeutic outcomes of adult acute leukemia, further study including more cases is needed.
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PMID:AC133 antigen as a prognostic factor in acute leukemia. 1148 69

Expression of cell surface markers on human hematopoietic cells has provided a method for characterizing subsets of cells with distinct biological functions. This is largely due to the ability to separate highly purified subpopulations of cells for comparative analysis. Relationships between the cell surface phenotype of these subpopulations and their proliferative and differentiative capacity have been instrumental in defining the hierarchical organization of cells comprising the human hematopoietic system. The identification and isolation of human hematopoietic cells expressing AC133, combined with use of in vitro and in vivo assays, has provided novel insights into the hematopoietic progenitor and stem cell compartment in the human. More recent studies have offered evidence that AC133 expression is not limited to primitive blood cells, but also defines unique cell populations in non-hematopoietic tissues. These findings will be reviewed here in the context of human hematopoiesis and the potential role and utility of AC133 expression in the human.
Leukemia 2001 Nov
PMID:AC133 expression in human stem cells. 1235 81

Recent reports indicate that activation of the Notch signaling pathway delays the differentiation of hematopoietic progenitors, suggesting that Notch may be used to develop novel ex vivo culture conditions for the expansion of primitive cells to be used in clinical transplantation. Here, we compare Notch expression and the effects of Jagged-1 treatment on highly purified subfractions of primitive CD34+ and CD34- human hematopoietic cells. Unlike response of cultured CD34+ cells, Jagged-1 treatment did not enhance the proliferation of CD34- cells, or promote differentiation of CD34- cells into CD34+ cells. While CD34+ and AC133-CD34- cells were shown to express all known forms of Notch receptors, Notch-3 and Notch-4 were not detected in AC133+CD34- cells. Similarly, CD34+ progeny of differentiated CD34- cells did not upregulate Notch-3 or Notch-4 upon differentiation, although transcripts for these genes were expressed in CD34+ arising from CD34+ CD38- parents, suggesting that the Notch receptor expression is tightly and differentially controlled. Fringe, known to inhibit Notch signaling in response to specific Notch ligands, was expressed in parent CD34- and CD34+ cells as well as their CD34+ progeny. We suggest that the inability of primitive CD34- cells to positively respond to Jagged-1 may be due in part to the absence of Notch-3 and Notch-4. Taken together, our study illustrates functional distinctiveness of the primitive CD34- subsets to CD34+ counterparts in relation to Jagged-1 response, and represents the first demonstration of a molecular difference among de novo isolated CD34+ compared to in vitro generated CD34+ cells arising from primitive CD34- or CD34+ parents.
Leukemia 2003 Jul
PMID:Differential response of primitive human CD34- and CD34+ hematopoietic cells to the Notch ligand Jagged-1. 1283 26

Acute myeloid leukemia (AML) may develop de novo or secondarily to myelodysplastic syndrome (MDS). Although the clinical outcome of MDS-related AML is worse than that of de novo AML, it is not easy to differentiate between these two clinical courses without a record of prior MDS. Large-scale profiling of gene expression by DNA microarray analysis is a promising approach with which to identify molecular markers specific to de novo or MDS-related AML. This approach has now been adopted with AC133-positive hematopoietic stem cell-like fractions purified from 10 individuals, each with either de novo or MDS-related AML of the M2 subtype. Sets of genes whose activity was associated with either disease course were identified. Furthermore, on the basis of the expression profiles of these genes, it was possible to predict correctly the clinical diagnosis for 17 (85%) of the 20 cases in a cross-validation trial. Similarly, different sets of genes were identified whose expression level was associated with clinical outcome after induction chemotherapy. These data suggest that, at least in terms of gene expression profiles, de novo AML and MDS-related AML are distinct clinical entities.
Leukemia 2003 Oct
PMID:DNA microarray analysis of hematopoietic stem cell-like fractions from individuals with the M2 subtype of acute myeloid leukemia. 1451 49

Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, there is overwhelming evidence in some malignancies that the tumor clone is heterogeneous with respect to proliferation and differentiation. In human leukemia, the tumor clone is organized as a hierarchy that originates from rare leukemic stem cells that possess extensive proliferative and self-renewal potential, and are responsible for maintaining the tumor clone. We report here the identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation. The increased self-renewal capacity of the brain tumor stem cell (BTSC) was highest from the most aggressive clinical samples of medulloblastoma compared with low-grade gliomas. The BTSC was exclusively isolated with the cell fraction expressing the neural stem cell surface marker CD133. These CD133+ cells could differentiate in culture into tumor cells that phenotypically resembled the tumor from the patient. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC.
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PMID:Identification of a cancer stem cell in human brain tumors. 1452 5

It has been suggested that bone marrow (BM)-derived hematopoietic stem cells transdifferentiate into tissue-specific stem cells (the so-called phenomenon of stem cell plasticity), but the possibility of committed tissue-specific stem cells pre-existing in BM has not been given sufficient consideration. We hypothesized that (i) tissue-committed stem cells circulate at a low level in the peripheral blood (PB) under normal steady-state conditions, maintaining a pool of stem cells in peripheral tissues, and their levels increase in PB during stress/tissue injury, and (ii) they could be chemoattracted to the BM where they find a supportive environment and that the SDF-1-CXCR4 axis plays a prominent role in the homing/retention of these cells to BM niches. We performed all experiments using freshly isolated cells to exclude the potential for 'transdifferentiation' of hematopoietic stem or mesenchymal cells associated with in vitro culture systems. We detected mRNA for various early markers for muscle (Myf-5, Myo-D), neural (GFAP, nestin) and liver (CK19, fetoprotein) cells in circulating (adherent cell-depleted) PB mononuclear cells (MNC) and increased levels of expression of these markers in PB after mobilization by G-CSF (as measured using real-time RT-PCR). Furthermore, SDF-1 chemotaxis combined with real-time RT-PCR analysis revealed that (i) these early tissue-specific cells reside in normal murine BM, (ii) express CXCR4 on their surface and (iii) can be enriched (up to 60 x) after chemotaxis to an SDF-1 gradient. These cells were also highly enriched within purified populations of murine Sca-1(+) BM MNC as well as of human CD34(+)-, AC133(+)- and CXCR4-positive cells. We also found that the expression of mRNA for SDF-1 is upregulated in damaged heart, kidney and liver. Hence our data provide a new perspective on BM not only as a home for hematopoietic stem cells but also a 'hideout' for already differentiated CXCR4-positive tissue-committed stem/progenitor cells that follow an SDF-1 gradient, could be mobilized into PB, and subsequently take part in organ/tissue regeneration.
Leukemia 2004 Jan
PMID:Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells 'hide out' in the bone marrow. 1458 76

CUB-domain-containing protein 1 (CDCP1) is a novel transmembrane molecule that is expressed in metastatic colon and breast tumors as well as on the surface of hematopoietic stem cells. In this study, we used multiparameter flow cytometry and antibodies against CDCP1 to analyze the expression of CDCP1 on defined hematopoietic cell subsets of different sources. In addition, CDCP1 expression on leukemic blasts and on cells with nonhematopoietic stem/progenitor cell phenotypes was determined. Here we demonstrate that a subset of bone marrow (BM), cord blood (CB), and mobilized peripheral blood (PB) CD34+ cells expressed this marker and that CDCP1 was detected on CD34(+)CD38- BM stem/progenitor cells but not on mature PB cells. Analysis of leukemic blasts from patients with acute lymphoblastic leukemia, acute myeloid leukemia, and chronic myeloid leukemia in blast crisis revealed that CDCP1 is predominantly expressed on CD34(+)CD133+ myeloid leukemic blasts. However, CDCP1 was not strictly correlated with CD34 and/or CD133 expression, suggesting that CDCP1 is a novel marker for leukemia diagnosis. Stimulation of CD34+ BM cells with CDCP1-reactive monoclonal antibody CUB1 resulted in an increased (approximately twofold) formation of erythroid colony-forming units, indicating that CDCP1 plays an important role in early hematopoiesis. Finally, we show that CDCP1 is also expressed on cells phenotypically identical to mesenchymal stem/progenitor cells (MSCs) and neural progenitor cells (NPCs). In conclusion, CDCP1 is not only a novel marker for immature hematopoietic progenitor cell subsets but also unique in its property to recognize cells with phenotypes reminiscent of MSC and NPC.
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PMID:CDCP1 identifies a broad spectrum of normal and malignant stem/progenitor cell subsets of hematopoietic and nonhematopoietic origin. 1515 10

In a 5-year survey of nonpromyelocytic/nonmonocytic acute myeloid leukemias (AMLs) diagnosed in the University of Washington Hematopathology Laboratory, we identified 19 cases containing distinctive, cup-like nuclear indentation in 10% or more of the blasts ('AML-cuplike'). Fourteen of these cases (74%) demonstrated near-complete loss of HLA-DR expression, while the other five cases showed partial loss of HLA-DR. A total of 16 of the cases (84%) demonstrated internal tandem duplication (ITD) of the Flt3 gene. When compared to a selected set of AMLs lacking this nuclear morphology, AML-cuplike was significantly more likely to lack HLA-DR and CD34 expression, to express CD123 without CD133, to have a normal karyotype, and to harbor the Flt3 ITD. To characterize AML-cuplike in an unselected series of AMLs, we analyzed 42 consecutive nonpromyelocytic/nonmonocytic AMLs diagnosed in our laboratory during a 6-month period in 2002. Strikingly, in this unselected series, there was a statistically significant coincidence of invaginated nuclear morphology, loss of HLA-DR, and presence of the Flt3 ITD beyond that expected if these three features were unrelated, suggesting that AMLs with these three features may represent a distinct AML subset.
Leukemia 2004 Oct
PMID:A distinctive nuclear morphology in acute myeloid leukemia is strongly associated with loss of HLA-DR expression and FLT3 internal tandem duplication. 1534 44


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