| 1. |
- Diffner, Eva, et al.
(författare)
-
Expression of VEGF and VEGF Receptors in Childhood Precursor B-cell Acute Lymphoblastic Leukemia Evaluated by Immunohistochemistry
- 2009
-
Ingår i: Journal of pediatric hematology/oncology (Print). - : Wolters Kluwer. - 1077-4114 .- 1536-3678. ; 31:9, s. 696-701
-
Tidskriftsartikel (refereegranskat)abstract
- Perturbation in the expression and signaling pathways of vascular endothelial growth factor (VEGF) has been linked to pathogenesis of hematologic malignancies. We investigated the expression and clinical importance of VEGF and two of its receptors, VEGFR-1 and VEGFR-2, in childhood precursor B-cell acute lymphoblastic leukemia (pre-B ALL) by using immunohistochemistry. These angiogenic proteins were expressed in the majority of leukemic bone marrow samples. Notably, pre-B ALL patients had significantly increased expression of VEGFR-1 compared with no expression in the nonmalignant group, indicating a link between VEGFR-1 protein expression and pre-B ALL. These novel findings suggest that VEGFR-1 may have clinical importance in childhood pre-B ALL.
|
|
| 2. |
- Diffner, Eva
(författare)
-
Responses to Tumour initiating factors and Regulation of Normal and Malignant Haematopoiesis
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The haematopoietic stem cell (HSC) resides within a specific environment enabling it to retain its self-renewal capacity or quiescent state. It is proposed that the HSC niche is hypoxic, a milieu within which the HSC is protected from intrinsic and extrinsic stimuli. We have investigated the haematopoietic phenotype of an HSC in a mouse model where hypoxia-regulated Vegfa expression is abrogated. In Vegfaδ/δ mice, the HRE in the Vegfa promoter has been deleted at both alleles, thereby inhibiting HIF-binding and subsequent activation of Vegfa expression following hypoxia. We show that hypoxic regulation of Vegfa expression within the haematopoietic system affects haematopoietic differentiation and numbers of HSCs to a small extent. Interestingly, Vegfa expression was shown to be reduced in highly purified HSCs from bone marrow of Vegfaδ/δ mice but not in mature cells, suggesting that the niche of the HSC is hypoxic. Acute lymphoblastic leukaemia (ALL) is the most common malignancy among children. Contemporary treatment protocols result in cure rates of 80-85% but 15-20% of children still experience relapse. A group of patients do therefore not benefit from conventional therapy underlining the urgent need to identify additional biomarkers at diagnosis. We have investigated the expression of VEGF-A, its receptors VEGFR-1 and VEGFR-2 as well as PTEN and SHP1 in childhood ALL using immunohistochemistry. We observed that the expression of VEGFR-1, PTEN and SHP1 in mononuclear cells of children with ALL were significantly different to the expression of mononuclear cells in children with no malignant disease. VEGFR-1, PTEN and SHP1 may be potential prognostic factors for childhood ALL. Chromosomal translocations are reported in approximately 65% of all acute leukaemias. Reports have identified leukaemic translocations in human peripheral blood of healthy individuals supporting the hypothesis that leukaemic transformation is a multistep process. The t(10;11)(p13-14;q14-21) translocation is a reciprocal translocation and forms both an in-frame CALM·AF10 and AF10·CALM fusion. The long latency period prior to the onset of leukaemia in CALM·AF10 mice models suggests that the fusion protein alone does not cause leukaemic development. We hypothesise that AF10·CALM is required for the full leukaemic phenotype. In an in vitro model, we found that t(10;11)(p13-14;q14-21) reciprocal fusions have individual effects on cell biology and, when found in combination, have either a more pronounced or an inhibitory effect on leukaemogenesis. This highlights the importance of examining both fusion proteins in a two transcript reciprocal translocation as they on their own may have individual characteristics.
|
|
| 3. |
- Gauffin, Fredrika, et al.
(författare)
-
Expresson of PTEN and SHP1, Ivestigated from Tissue Microarrays in Pediatric Acute Lymphoblastic, Leukemia
- 2009
-
Ingår i: Pediatric Hematology & Oncology. - : Informa UK Limited. - 0888-0018 .- 1521-0669. ; 26:1, s. 48-56
-
Tidskriftsartikel (refereegranskat)abstract
- PTEN and SHP1 are tumor suppressor genes involved in the regulation of cell cycle control and apoptosis. The authors investigated the protein expression of PTEN and SHP1, by immunohistochemistry in tissue microarrays from bone marrow samples in children, diagnosed with acute lymphoblastic leukaemia and nonmalignant controls. PTEN was overexpressed in diagnostic ALL samples, while SHP1 showed a low expression. Both proteins showed a significant difference in expression compared to nonmalignant controls. The roles of PTEN and SHP1 are not well investigated in pediatric leukemia and could in the future play a role as prognostic factors.
|
|
| 4. |
- Rehn, Matilda, et al.
(författare)
-
Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche.
- 2011
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:6, s. 1534-1543
-
Tidskriftsartikel (refereegranskat)abstract
- Hypoxia is emerging as an important characteristic of the hematopoietic stem cell (HSC) niche, but the molecular mechanisms contributing to quiescence, self-renewal, and survival remain elusive. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis and hematopoiesis. Its expression is commonly regulated by hypoxia-inducible factors (HIF) that are functionally induced in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE). Vegfa is indispensable for HSC survival, mediated by a cell-intrinsic, autocrine mechanism. We hypothesized that a hypoxic HSC microenvironment is required for maintenance or upregulation of Vegfa expression in HSCs and therefore crucial for HSC survival. We have tested this hypothesis in the mouse model Vegfa(δ/δ), where the HRE in the Vegfa promoter is mutated, preventing HIF binding. Vegfa expression was reduced in highly purified HSCs from Vegfa(δ/δ) mice, showing that HSCs reside in hypoxic areas. Loss of hypoxia-regulated Vegfa expression increases the numbers of phenotypically defined hematopoietic stem and progenitor cells. However, HSC function was clearly impaired when assessed in competitive transplantation assays. Our data provide further evidence that HSCs reside in a hypoxic microenvironment and demonstrate a novel way in which the hypoxic niche affects HSC fate, via the hypoxia-Vegfa axis.
|
|
