The SHB adaptor protein in human and murine leukemia

Sammanfattning: 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.