| 1. |
- Kuchenbauer, Florian, et al.
(författare)
-
Comprehensive analysis of mammalian miRNA* species and their role in myeloid cells.
- 2011
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:12, s. 3350-8
-
Tidskriftsartikel (refereegranskat)abstract
- Processing of pre-miRNA through Dicer1 generates an miRNA duplex that consists of an miRNA and miRNA* strand. Despite the general view that miRNA*s have no functional role, we further investigated miRNA* species in 10 deep-sequencing libraries from mouse and human tissue. Comparisons of miRNA/miRNA* ratios across the miRNA sequence libraries revealed that 50% of the investigated miRNA duplexes exhibited a highly dominant strand. Conversely, 10% of miRNA duplexes showed a comparable expression of both strands, whereas the remaining 40% exhibited variable ratios across the examined libraries, as exemplified by miR-223/miR-223* in murine and human cell lines. Functional analyses revealed a regulatory role for miR-223* in myeloid progenitor cells, which implies an active role for both arms of the miR-223 duplex. This was further underscored by the demonstration that miR-223 and miR-223* targeted the insulin-like growth factor 1 receptor/phosphatidylinositol 3-kinase axis and that high miR-223* levels were associated with increased overall survival in patients with acute myeloid leukemia. Thus, we found a supporting role for miR-223* in differentiating myeloid cells in normal and leukemic cell states. The fact that the miR-223 duplex acts through both arms extends the complexity of miRNA-directed gene regulation of this myeloid key miRNA.
|
|
| 2. |
- Lundin, Catarina, et al.
(författare)
-
High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome
- 2012
-
Ingår i: Genes, Chromosomes and Cancer. - Malden : Wiley-Blackwell. - 1045-2257 .- 1098-2264. ; 51:2, s. 196-206
-
Tidskriftsartikel (refereegranskat)abstract
- Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as less than10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrentdup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.
|
|
| 3. |
|
|
| 4. |
- Andersen, Mette K., et al.
(författare)
-
Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13) : clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols
- 2011
-
Ingår i: British Journal of Haematology. - Oxford : Wiley. - 0007-1048 .- 1365-2141. ; 155:2, s. 235-243
-
Tidskriftsartikel (refereegranskat)abstract
- The translocation t(1;19)(q23;p13)/der(19) t(1;19) is a risk stratifying aberration in childhood B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the Nordic countries. We have identified 47 children/adolescents with t(1;19)/der(19) t(1;19)-positive BCP ALL treated on two successive Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols between 1992 and 2007 and have reviewed the clinical and cytogenetic characteristics of these cases, comprising 1.8% of all cases. The translocation was balanced in 15 cases (32%) and unbalanced in 29 cases (62%). The most common additional chromosome abnormalities were del(9p), i(9q), del(6q), and del(13q). The median age was 7 years, the median white blood cell (WBC) count was 16 x 10(9)/l, and the female/male ratio was 1.2. The predicted event-free survival (EFS) at 5 and 10 years was 0.79, whereas the predicted overall survival (OS) at 5 and 10 years was 0.85 and 0.82, respectively. Nine patients had a bone marrow relapse after a median of 23 months; no patient had a central nervous system relapse. Additional cytogenetic abnormalities, age, gender, WBC count or whether the t(1;19) was balanced or unbalanced did not influence EFS or OS. Compared to cases with t(12,21) and high hyperdiploidy, EFS was similar, but overall survival was worse in patients with t(1;19)/der(19) t(1;19) (P = 0.004).
|
|
| 5. |
- Argiropoulos, Bob, et al.
(författare)
-
Linkage of the potent leukemogenic activity of Meis1 to cell-cycle entry and transcriptional regulation of cyclin D3.
- 2010
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 115:20, s. 4071-82
-
Tidskriftsartikel (refereegranskat)abstract
- MEIS1 is a three-amino acid loop extension class homeodomain-containing homeobox (HOX) cofactor that plays key roles in normal hematopoiesis and leukemogenesis. Expression of Meis1 is rate-limiting in MLL-associated leukemias and potently interacts with Hox and NUP98-HOX genes in leukemic transformation to promote self-renewal and proliferation of hematopoietic progenitors. The oncogenicity of MEIS1 has been linked to its transcriptional activation properties. To further reveal the pathways triggered by Meis1, we assessed the function of a novel engineered fusion form of Meis1, M33-MEIS1, designed to confer transcriptional repression to Meis1 target genes that are otherwise up-regulated in normal and malignant hematopoiesis. Retroviral overexpression of M33-Meis1 resulted in the rapid and complete eradication of M33-Meis1-transduced normal and leukemic cells in vivo. Cell-cycle analysis showed that M33-Meis1 impeded the progression of cells from G(1)-to-S phase, which correlated with significant reduction of cyclin D3 levels and the inhibition of retinoblastoma (pRb) hyperphosphorylation. We identified cyclin D3 as a direct downstream target of MEIS1 and M33-MEIS1 and showed that the G(1)-phase accumulation and growth suppression induced by M33-Meis1 was partially relieved by overexpression of cyclin D3. This study provides strong evidence linking the growth-promoting activities of Meis1 to the cyclin D-pRb cell-cycle control pathway.
|
|
| 6. |
|
|
| 7. |
- Aurelius, Johan, 1980, et al.
(författare)
-
Chronic myeloid leukemic cells trigger poly(ADP-ribose) polymerase-dependent inactivation and cell death in lymphocytes.
- 2013
-
Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 1938-3673 .- 0741-5400. ; 93:1, s. 155-160
-
Tidskriftsartikel (refereegranskat)abstract
- NK cells and T cells are commonly dysfunctional in CML, and their status may determine the course of disease. We aimed to define the molecular mechanisms of leukemia-induced immunosuppression with focus on the role of ROS and the PARP-1 pathway of cell death. Malignant granulocytes from patients with BCR-ABL-positive CML expressed the oxygen radical-producing enzyme NOX, produced large amounts of ROS, and triggered extensive cell death in NK cells. Inhibition of PARP-1 maintained NK cell viability in cocultures with suppressive leukemic cells. Under conditions of oxidative stress, PARP-1 inhibition upheld the capacity of NK cells to kill myeloid leukemic cells, in addition to restoring the proliferation and cytokine production of NK cells and cytotoxic T cells. Our findings are suggestive of a novel pathway of relevance to immunosuppression in CML.
|
|
| 8. |
- Aurelius, Johan, 1980, et al.
(författare)
-
Monocytic AML cells inactivate antileukemic lymphocytes: role of NADPH oxidase/gp91(phox) expression and the PARP-1/PAR pathway of apoptosis.
- 2012
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 119:24, s. 5832-7
-
Tidskriftsartikel (refereegranskat)abstract
- Dysfunction of T cells and natural killer (NK) cells has been proposed to determine the course of disease in acute myeloid leukemia (AML), but only limited information is available on the mechanisms of lymphocyte inhibition. We aimed to evaluate to what extent human malignant AML cells use NADPH oxidase-derived reactive oxygen species (ROS) as an immune evasion strategy. We report that a subset of malignant myelomonocytic and monocytic AML cells (French-American-British [FAB] classes M4 and M5, respectively), recovered from blood or BM of untreated AML patients at diagnosis, expressed the NADPH oxidase component gp91(phox). Highly purified FAB M4/M5 AML cells produced large amounts of ROS on activation and triggered poly-[ADP-ribose] polymerase-1-dependent apoptosis in adjacent NK cells, CD4(+) T cells, and CD8(+) T cells. In contrast, immature (FAB class M1) and myeloblastic (FAB class M2) AML cells rarely expressed gp91(phox), did not produce ROS, and did not trigger NK or T-cell apoptosis. Microarray data from 207 AML patients confirmed a greater expression of gp91(phox) mRNA by FAB-M4/M5 AML cells than FAB-M1 cells (P < 10(-11)) or FAB-M2 cells (P < 10(-9)). Our data are suggestive of a novel mechanism by which monocytic AML cells evade cell-mediated immunity.
|
|
| 9. |
- Aurelius, Johan, 1980, et al.
(författare)
-
Remission maintenance in acute myeloid leukemia: impact of functional histamine H-2 receptors expressed by leukemic cells
- 2012
-
Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 97:12, s. 1904-1908
-
Tidskriftsartikel (refereegranskat)abstract
- Post-consolidation immunotherapy with histamine dihydrochloride and interleukin-2 has been shown to improve leukemia-free survival in acute myeloid leukemia in a phase III trial. For this study, treatment efficacy was determined among 145 trial patients with morphological forms of acute myeloid leukemia as defined by the French-American-British classification. Leukemia-free survival was strongly improved in M4/M5 (myelomonocytic/monocytic) leukemia but not in M2 (myeloblastic) leukemia. We also analyzed histamine H-2 receptor expression by leukemic cells recovered from 26 newly diagnosed patients. H-2 receptors were typically absent from M2 cells but frequently expressed by M4/M5 cells. M4/M5 cells, but not M2 cells, produced reactive oxygen species that triggered apoptosis in adjacent natural killer cells. These events were significantly inhibited by histamine dihydrochloride. Our data demonstrate the presence of functional histamine H2 receptors on human AML cells and suggest that expression of these receptors by leukemic cells may impact on the effectiveness of histamine-based immunotherapy.
|
|
| 10. |
|
|
