Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Several studies have shown defective progenitor-stromal interactions in chronic myeloid leukemia (CML), and adhesive defects induced by BCR/ABL have been described. However, controversial results have been reported, and the role of the stroma in abnormal development of the hematopoietic system is not clear. In this study, CML hematopoietic and irradiated stromal cells were co-cultured in different combinations for 10 or 21 days. Maintenance of viable cells was dependent both on the sources of hematopoietic progenitors and stromal adherent layers, with normal cells performing better than their leukemic counterparts. The frequency of CD34(+) CD38(-) cells in the non-adherent fraction was more related to the source of hematopoietic cells than of stroma, and hematopoietic cells from normal subjects showed better performance. The simultaneous analysis of different combinations of normal and leukemic precursor cells and stromal layers, as done in the present work, suggests that the outcome of the interaction depends on characteristics of both compartments. This hematopoietic system development is influenced by intrinsic qualities of both hematopoietic stem cells and the supportive stroma.
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PMID:Interaction between normal and CML hematopoietic progenitors and stroma influences abnormal hematopoietic development. 1518 18

Acute myeloid leukemia (AML) has a poor prognosis due to treatment-resistant relapses. A humanized anti-CD33 antibody (Mylotarg) showed a limited response rate in relapsed AML. To discover novel AML antibody targets, we selected a panel of single chain Fv fragments using phage display technology combined with flow cytometry on AML tumor samples. One selected single chain Fv fragment broadly reacted with AML samples and with myeloid cell lineages within peripheral blood. Expression cloning identified the antigen recognized as C-type lectin-like molecule-1 (CLL-1), a previously undescribed transmembrane glycoprotein. CLL-1 expression was analyzed with a human anti-CLL-1 antibody that was generated from the single chain Fv fragment. CLL-1 is restricted to the hematopoietic lineage, in particular to myeloid cells present in peripheral blood and bone marrow. CLL-1 is absent on uncommitted CD34(+)/CD38(-) or CD34(+)/CD33(-) stem cells and present on subsets of CD34(+)/CD38(+) or CD34(+)/CD33(+) progenitor cells. CLL-1 is not expressed in any other tissue. In contrast, analysis of primary AMLs demonstrated CLL-1 expression in 92% (68 of 74) of the samples. As an AML marker, CLL-1 was able to complement CD33, because 67% (8 of 12) of the CD33(-) AMLs expressed CLL-1. CLL-1 showed variable expression (10-60%) in CD34(+) cells in chronic myelogenous leukemia and myelodysplastic syndrome but was absent in 12 of 13 cases of acute lymphoblastic leukemia. The AML reactivity combined with the restricted expression on normal cells identifies CLL-1 as a novel potential target for AML treatment.
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PMID:C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia. 1554 16

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

Dasatinib (BMS-354825), a novel dual SRC/BCR-ABL kinase inhibitor, exhibits greater potency than imatinib mesylate (IM) and inhibits the majority of kinase mutations in IM-resistant chronic myeloid leukemia (CML). We have previously demonstrated that IM reversibly blocks proliferation but does not induce apoptosis of primitive CML cells. Here, we have attempted to overcome this resistance with dasatinib. Primitive IM-resistant CML cells showed only single-copy BCR-ABL but expressed significantly higher BCR-ABL transcript levels and BCR-ABL protein compared with more mature CML cells (P = .031). In addition, CrKL phosphorylation was higher in the primitive CD34(+)CD38(-) than in the total CD34(+) population (P = .002). In total CD34(+) CML cells, IM inhibited phosphorylation of CrKL at 16 but not 72 hours, consistent with enrichment of an IM-resistant primitive population. CD34(+)CD38(-) CML cells proved resistant to IM-induced inhibition of CrKL phosphorylation and apoptosis, whereas dasatinib led to significant inhibition of CrKL phosphorylation. Kinase domain mutations were not detectable in either IM or dasatinib-resistant primitive CML cells. These data confirm that dasatinib is more effective than IM within the CML stem cell compartment; however, the most primitive quiescent CML cells appear to be inherently resistant to both drugs.
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PMID:Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. 1724 89

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

The leukemic stem cells in patients with chronic myeloid leukemia (CML) are well known to be clinically resistant to conventional chemotherapy and may also be relatively resistant to BCR-ABL-targeted drugs. Here we show that the lesser effect of imatinib mesylate (IM) on the 3-week output of cells produced in vitro from lin(-)CD34(+)CD38(-) CML (stem) cells compared with cultures initiated with the CD38(+) subset of lin(-)CD34(+) cells is markedly enhanced (>10-fold) when conditions of reduced growth factor stimulation are used. Quantitative analysis of genes expressed in these different CML subsets revealed a differentiation-associated decrease in IL-3 and G-CSF transcripts, a much more profound decrease in expression of BCR-ABL than predicted by changes in BCR expression, decreasing expression of ABCB1/MDR and ABCG2 and increasing expression of OCT1. p210(BCR-ABL) and kinase activity were also higher in the lin(-)CD34(+)CD38(-) cells and formal evidence that increasing BCR-ABL expression decreases IM sensitivity was obtained from experiments with a cell line model. Nevertheless, within the entire CD34(+) subset of CML cells, BCR-ABL expression was not strongly affected by changes in cell cycle status. Taken together, these results provide the first evidence of multiple mechanisms of innate IM resistance in primitive and quiescent CML cells.
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PMID:Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. 1733 Jan 1

CML (chronic myeloid leukaemia) is a myeloproliferative disease that originates in an HSC (haemopoietic stem cell) as a result of the t(9;22) translocation, giving rise to the Ph (Philadelphia chromosome) and bcr-abl oncoprotein. The disease starts in CP (chronic phase), but as a result of genomic instability, it progresses over time to accelerated phase and then to BC (blast crisis), becoming increasingly resistant to therapy. bcr-abl is a constitutively active tyrosine kinase that has been targeted by TKIs (tyrosine kinase inhibitors), including IM (imatinib mesylate), nilotinib and dasatinib. We have developed various flow cytometry techniques to enable us to isolate candidate CML stem cells from CP patients at diagnosis that efflux Hoechst dye, express CD34, lack CD38 and are cytokine-non-responsive in culture over periods of up to 12 days in growth factors. These stem cells have been shown to regenerate bcr-abl-positive haemopoiesis in immunocompromised mice upon transplantation. We previously demonstrated that IM was antiproliferative for CML stem cells but did not induce apoptosis. Clinical experience now confirms that IM may not target CML stem cells in vivo with few patients achieving complete molecular remission and relapse occurring rapidly upon drug withdrawal. Our recent efforts have focused on understanding why CML stem cells are resistant to IM and on trying to find novel ways to induce apoptosis of this population. We have shown that CML stem cells express very high levels of functional wild-type bcr-abl; no kinase domain mutations have been detected in the stem cell population. Dasatinib, a more potent multitargeted TKI than IM, inhibits bcr-abl activity more efficiently than IM but still does not induce apoptosis of the stem cell population. Most recently, we have tested a number of novel drug combinations and found that FTIs (farnesyl transferase inhibitors) have activity against CML. BMS-214662 is the most effective of these and induces apoptosis of phenotypically and functionally defined CML stem cells in vitro, as a single agent and in combination with IM or dasatinib. The effect against CML stem cells is selective with little effect on normal stem cells. The drug is also effective against BC CML stem cells and equally effective against wild-type and mutant bcr-abl, including the most resistant mutant T315I. In association with apoptosis, there is activation of caspase 8 and caspase 3, inhibition of the MAPK pathway, IAP-1 (inhibitor of apoptosis protein-1), NF-kappaB (nuclear factor kappaB) and iNOS (inducible nitric oxide synthase). Furthermore, BMS-214662 synergizes with MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitors, suggesting a second mechanism other that RAS inhibition for induction of apoptosis. Our intentions are now to explore the activity of BMS-214662 in other cancer stem cell disorders and to move this preclinical work to a clinical trial combining dasatinib with BMS-214662 in CML.
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PMID:Characterization of cancer stem cells in chronic myeloid leukaemia. 1795 48

We constructed a "biomimetic osteoblast niche" with bio-derived bone as a scaffold, on which we seeded marrow mesenchymal stem cells (MSCs) from CML patients, and induced the MSCs to differentiate into osteoblasts. Bone marrow mononuclear cells from CML patients were cultured in the biomimetic niche (3D culture system) or a 2D culture system with the induced MSCs/osteoblasts as a feeder cell layer for 2 and 5 weeks without adding exogenous cytokines. Cultured cells were analyzed regarding their phenotypes and functions using flow cytometry, colony-forming unit (CFU) assay and long-term culture-initiating cells (LTC-IC) assay. All cultured and colony cells in the LTC-IC assay were collected and analyzed by fluorescent in situ hybridization to identify Ph (bcr/abl)-positive cells. Our results showed that all parameters were higher in the 3D than in the 2D system, either at 2 or 5 weeks, i.e., regarding the number of CD34(+) cells (8,277.00 vs. 4,490.75 or 2,276.75 vs. 786.00 per well on average, respectively), number of CD34(+)/CD38(-) cells (1,207.50 vs. 474.25 or 497.25 vs. 114.25 per well on average, respectively), numbers of CFUs (103.33 vs. 79 or 47.0 vs. 21.67/10(5) MNCs; 189.33 vs. 131.00 or 10.33 vs. 3.67 per well on average, respectively), frequency of LTC-ICs (2.23 x 10(-5) vs. 1.40 x 10(-5) or 1.86 x 10(-5) vs. 0.64 x 10(-5), respectively) and number of remaining LTC-ICs (2.80 vs. 2.03 or 0.46 vs. 0.07 per well on average, respectively). The Ph (bcr/abl)-positive cell fraction was reduced in both systems during culture, but in the 3D system, it was not as rapid as in the 2D system and showed a leukemic predominance. In conclusion, our "biomimetic osteoblast niche" might provide a more adaptive microenvironment for leukemic stem/progenitor cell growth. The biological characteristics of leukemic stem/progenitor cells were partially maintained. It was suggested that the 3D biomimetic niche might be a new tool for studying the behaviors of leukemic hematopoietic stem cells/hematopoietic progenitor cells in vitro.
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PMID:Long-term culture of leukemic bone marrow primary cells in biomimetic osteoblast niche. 1966 60

Stem cells of acute myeloid leukemia (AML) have been identified as immunodeficient mouse-repopulating cells with a Lin(-)CD34(+)38(-) phenotype similar to normal hematopoietic stem cells. To identify the leukemia-propagating stem cell fraction of Philadelphia chromosome-positive (Ph(+)) leukemia, we serially transplanted human leukemia cells from patients with chronic myeloid leukemia blast crisis (n = 3) or Ph(+) acute lymphoblastic leukemia (n = 3) into NOD/SCID/IL-2Rgammac(-/-) mice. Engrafted cells were almost identical to the original leukemia cells as to phenotypes, IGH rearrangements, and karyotypes. CD34(+)CD38(-)CD19(+), CD34(+)38(+)CD19(+), and CD34(-)CD38(+)CD19(+) fractions could self-renew and transfer the leukemia, whereas the CD34(-)CD38(+)CD19(+) fraction did not stably propagate in NOD/SCID mice. These findings suggest that leukemia-repopulating cells in transformed Ph(+) leukemia are included in a lineage-committed but multilayered fraction, and that CD34(+) leukemia cells potentially emerge from CD34(-) populations.
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PMID:Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD/SCID/IL-2Rgammac-/- mice. 2002 84


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