| 1. |
- Woll, Petter S, et al.
(författare)
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Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo.
- 2014
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Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 25:6, s. 794-808
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Tidskriftsartikel (refereegranskat)abstract
- Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.
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| 2. |
- Castor, Anders, et al.
(författare)
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Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia
- 2005
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 11:6, s. 630-637
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Tidskriftsartikel (refereegranskat)abstract
- The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.
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| 3. |
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| 4. |
- Grövdal, Michael, et al.
(författare)
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Maintenance treatment with azacytidine for patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia following MDS in complete remission after induction chemotherapy
- 2010
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 150:3, s. 293-302
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Tidskriftsartikel (refereegranskat)abstract
- This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0.003). 5-azacytidine treatment, at a dose of 60 mg/m(2) was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.
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| 5. |
- Grövdal, Michael, et al.
(författare)
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Negative effect of DNA hypermethylation on the outcome of intensive chemotherapy in older patients with high-risk myelodysplastic syndromes and acute myeloid leukemia following myelodysplastic syndrome
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:23, s. 7107-7112
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. EXPERIMENTAL DESIGN: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment. RESULTS: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. CONCLUSIONS: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.
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| 6. |
- Jørkov, Andreas Schjellerup, et al.
(författare)
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Immune response in blood and tumour tissue in patients with metastatic malignant melanoma treated with IL-2, IFN alpha and histamine dihydrochloride.
- 2003
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Ingår i: Anticancer research. - 0250-7005. ; 23:1B, s. 537-42
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Tidskriftsartikel (refereegranskat)abstract
- Interleukin-2 and interferon-alpha are pleiotropic immuno-activating cytokines with clinical efficacy in malignant melanoma. The anti-melanoma activity of these cytokines is believed to result from the triggering of lymphocyte-mediated killing of tumour cells. In ongoing clinical trials, histamine dihydrochloride is used as an adjuvant to IL-2 and IFN-alpha with a view to protecting lymphocytes from oxidative inhibition induced by tumour-infiltrating monocyte/macrophages. In this study, we have serially monitored mononuclear cells in peripheral blood and tumour biopsies from 13 patients with metastatic malignant melanoma treated under a protocol comprising histamine, IFN-alpha and low-dose IL-2. One complete and 3 partial responses were observed, while 3 patients had stable disease and 6 progressed. A trend towards a gradual increase in the absolute number of circulating CD56+/CD3- NK cells in patients maintaining stable disease during therapy was noted. In tumour tissues, the extent of leukocyte infiltration prior to treatment correlated with tumour response. Additional infiltration by NK cells (CD56+) and monocytes during treatment was seen only in responding patients. Patients with progressive disease exhibited a low density of leukocytes infiltrating tumour tissues at the onset of treatment as compared to the surrounding tissues. Our data indicate that the degree and localization of mononuclear infiltration before and during immunotherapy under this protocol may determine therapeutic anti-tumour responses.
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| 7. |
- Nilsson, Lars, et al.
(författare)
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Involvement and functional impairment of the CD34(+)CD38(-)Thy-1(+) hematopoietic stem cell pool in myelodysplastic syndromes with trisomy 8.
- 2002
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 100:1, s. 259-267
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Tidskriftsartikel (refereegranskat)abstract
- Clonality studies of mature cells suggest that the primary transformation event in myelodysplastic syndrome (MDS) most frequently occurs in a myeloid-restricted progenitor, a hypothesis supported by recent studies of purified CD34(+)Thy1(+) hematopoietic stem cells (HSCs) in cases with trisomy 8 (+8). In contrast, we recently demonstrated that a lymphomyeloid HSC is the target for transformation in MDS cases with del(5q), potentially reflecting heterogeneity within MDS. However, since +8 is known to frequently be a late event in the MDS transformation process, it remained a possibility that CD34(+)CD38(-)Thy1(+) HSC disomic for chromosome 8 might be part of the MDS clone. In the present studies, although a variable fraction of CD34(+)CD38(-)Thy1(+) cells were disomic for chromosome 8, they did not possess normal HSC activity in long-term cultures and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Mixing experiments with normal CD34(+)CD38(-) cells suggested that this HSC deficiency was intrinsic and not mediated by indirect mechanisms. Furthermore, investigation of 4 MDS cases with combined del(5q) and +8 demonstrated that the +8 aberration was always secondary to del(5q). Whereas del(5q) invariably occurs in CD34(+)CD38(-)Thy-1(+) HSCs, the secondary +8 event might frequently arise in progeny of MDS HSCs. Thus, CD34(+)CD38(-)Thy1(+) HSCs are invariably part of the MDS clone also in +8 patients, and little HSC activity can be recovered from the CD34(+) CD38(-)Thy1(+) HSC. Finally, in advanced cases of MDS, the MDS reconstituting activity is exclusively derived from the minor CD34(+)CD38(-) HSC population, demonstrating that MDS stem cells have a similar phenotype as normal HSCs, potentially complicating the development of autologous transplantation for MDS.
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| 8. |
- Tefferi, Ayalew, et al.
(författare)
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Myeloproliferative neoplasms - a global view
- 2022
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Ingår i: British Journal of Haematology. - Chichester, United Kingdom : Wiley-Blackwell. - 0007-1048 .- 1365-2141. ; 198:6, s. 953-564
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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