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Coming dissertations at MedFak

  • The SHB adaptor protein in human and murine leukemia Author: Maria Jamalpour Link: Publication date: 2020-11-20 13:47

    The SHB adaptor protein operates downstream of tyrosine kinase receptors. It has been found previously that Shb deficiency in hematopoietic stem cells (HSCs) results in less proliferation and failure to maintain the myeloid compartment over time. Based on these findings, I have investigated the effects of Shb deletion on the development of different types of murine as well as human leukemia.     

    The absence of Shb exacerbated p210 BCR-ABL induced myeloid leukemia due to an elevated level of focal adhesion kinase (FAK) activity and high expression of the cytokines Interleukin-6 (IL-6) and granulocyte-colony stimulating factor (G-CSF), resulting in an increased number of neutrophils in the blood.

    When the effects of the SHB gene in human leukemia were investigated, it was found that SHB gene expression relates to the survival of patients suffering from acute myeloid leukemia and acute promyelocytic leukemia. Additionally, a group of genes co-expressed with SHB demonstrated immunological phenotypes and vascular and apoptotic characteristics.

    These findings prompted further investigations of the effects of Shb deficiency on neutrophilic, B-cell, and T-cell leukemia. Wild type or Shb knockout bone marrow cells expressing the oncogenes (CSF3R-T618I, p190 BCR-ABL, and Kras-G12D) were transplanted into wild type recipients. As a result, a more aggressive disease with shorter latency and decreased IL-6 and G-CSF expression was observed in the neutrophilic model whereas lower expression of IL-7 and C-X-C motif chemokine 12 (CXCL-12) was observed in the B-cell model in the absence of Shb. In the B-cell and T-cell leukemia models, lack of Shb altered disease characteristics without affecting latency.

    The effect of Shb deficiency in the progression of MLL-AF9-induced mixed-lineage leukemia was also investigated. Bone marrow cells from wild type and Shb knockout mice were transduced with the MLL-AF9 gene. The absence of Shb resulted in a higher cell proliferation rate in in vitro culture, whereas in an in vivo setting, latency was increased compared to the wild type counterparts. Alterations in cytokine expression, especially IL-6 and IL-1b, constituted a likely explanation for this difference.

    In conclusion, SHB plays a pleiotropic role in shifting phenotypic responses in different leukemia models. Therefore, personalized medicine treatment should be planned based on the type of leukemia in relation to SHB gene expression.

  • Molecular studies of endocrine tumors : Insights from genetics and epigenetics Author: Samuel Backman Link: Publication date: 2020-11-19 10:25

    Endocrine tumors may be benign or malignant and may occur in any of the hormone producing tissues. They share several biological characteristics, including a low mutation-burden, and may co-occur in several hereditary tumor syndromes. The aim of this thesis was to identify genetic and epigenetic aberrations in endocrine tumors.

    In paper I we performed a comprehensive DNA methylation analysis of 39 pheochromocytomas/paragangliomas as well as 4 normal adrenal medullae on the HumanMethylation27 BeadChip array. We validated two previously described clusters based on DNA methylation with distinct genetic associations.

    In Paper II we performed a transcriptomic analysis of 15 aldosterone producing adenomas. CTNNB1-mutated tumors were found to form a distinct subgroup based on gene expression and to share gene expression similarities with non-aldosterone producing adrenocortical tumors with CTNNB1 mutations, including overexpression of AFF3 and ISM1.

    In paper III we used whole genome sequencing to identify germline genetic variants in 14 patients with Multiple Endocrine Neoplasia type 1 previously found to be wildtype for the MEN1 gene on routine clinical testing. Three patients were found to carry previously undetected MEN1 mutations. Two patients were confirmed to have phenocopies caused by variants affecting CASR or CDC73. In total 9/14 patients were not found to have a disease-causing germline variant, suggesting that the syndrome may in some cases be due to chance co-occurrence of several sporadic tumors.

    In paper IV RNA-Seq and whole genome sequencing of a cohort of SI-NETs selected on the basis of unusually short or long survival was performed in order to identify disease causing genes and potential prognostic factors. We confirmed known genetic aberrations and found rare variants in known cancer driver genes. Based on gene expression two clusters that differ in prognosis were detected. Moreover, through integration of copy number variation data and gene expression, we identied novel potential disease causing genes.

  • Insights into the Effects of Type 2 Diabetes on Bone Health Author: Adam Mitchell Link: Publication date: 2020-11-19 09:22

    Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of hip fracture, despite a stable or even greater bone mineral density (BMD). Bone area is linked to hip fracture risk independent of BMD and smaller bone area has been reported in T2DM subjects at the radius and tibia, but information at the hip is lacking. The Mediterranean diet is associated with a lower risk of hip fracture yet the mechanisms are unclear. The diet’s effect on T2DM status may be a possible mechanism. This thesis aims to discern the effects fasting glucose levels and T2DM have on bone.

    In paper I, clinical cut offs of fasting glucose used to define T2DM, were used to explore the association with BMD, bone area and bone turnover markers in the Swedish mammography cohort clinical (SMCC) and the Uppsala longitudinal study of adult men (ULSAM). T2DM was associated with greater BMD yet lower bone area at the total hip when compared to those without T2DM. T2DM was also associated with lower levels of bone turnover markers.

    In paper II, a Mendelian randomisation (MR) study was used to assess the potential causal effects of genetically predicted fasting glucose concentrations on bone area and BMD in partici-pants from SMCC, the prospective investigation in the vasculature of Uppsala seniors (PIVUS) and ULSAM. Results suggest an increase in genetically predicted fasting glucose concentrations may be a causal risk factor for lower bone area and possibly greater BMD.

    In paper III, the association between T2DM status and change in bone area and BMD over 8 years, was analysed in the SMCC, PIVUS and ULSAM. Those with incident T2DM had a lesser expansion in bone area at the total hip compared to those without T2DM.

    In paper IV, causal inference mediation analyses were used to estimate the direct effect of Mediterranean diet on the risk of hip fracture and the possible mediating effects of T2DM and BMI in the Swedish mammography cohort (SMC) and the cohort of Swedish men (COSM). Results showed a direct effect of the Mediterranean diet on the risk of hip fracture but ruled out the effects of T2DM and BMI as major mediators.

    In summary, T2DM and fasting glucose were associated with lower bone area at the hip. This may provide important mechanistic evidence as to why those with T2DM have a greater risk of hip fracture. We cannot rule out mediation or counteracting effects but there is an effect of Medi-terranean diet on hip fracture that does not go through T2DM and BMI.