Targeting key survival signaling pathways for the treatment of leukemia

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Sammanfattning

Leukemia is a cancer of the blood cells that has traditionally been treated with unselective chemotherapeutic agents. Advances in molecular biology and sequencing technologies have revolutionized the understanding of molecular and genetic factors in leukemia pathogenesis. Each leukemia patient harbors a unique set of genetic abnormalities, which result in impaired regulation of cell proliferation and differentiation. Increased cell proliferation is commonly mediated through overactive signaling cascades, such as JAK/STAT, PI3K/AKT/mTOR and MAPK pathways. The improved understanding of the molecular pathobiology has led to the development of small molecule inhibitors that can directly bind to target proteins and inhibit aberrant signaling. However, the molecular landscape of rare types of leukemia has not been comprehensively studied and our understanding of the relationship between cancer genotype, phenotype and drug function is limited. In study I, we aimed to identify novel driver mutations in large granular lymphocyte (LGL) leukemia. Earlier, our research group discovered that 40% of LGL leukemia patients had activating point mutations in the STAT3 gene. By using exome and targeted sequencing we identified 4/211 patients to carry an activating STAT5B mutation in the SH2 domain (N642H and Y640F). In study II, we identified STAT5B mutations in 6/68 (8%) T-cell acute lymphoblastic leukemia (T-ALL) patients. The finding represents a novel mechanism leading to the activation of the IL7R/JAK/STAT5 pathway. Our initial results also suggest that hyperactive STAT5B might be involved in the overexpression of anti-apoptotic BCL-xL. In study III, using a functional reporter assay we screened 306 oncology compounds to find potential hits that can decrease the cellular activity of mutant STAT3. The most potent targeted compounds inhibiting STAT3 activity were cyclin-dependent kinase (CDK), mammalian target of rapamycin (mTOR), heat shock protein 90 (Hsp90), and Janus kinase (JAK) inhibitors. Among these compounds only the Hsp90 inhibitors effectively inhibited both the mutant and wild type STAT3 phosphorylation and activity. In study IV, we developed a flow cytometry-based drug screening assay to assess cell population specific drug responses in heterogenous AML samples. Using the assay, we were able to simultaneously measure the drug responses of leukemic blasts, more mature leukemic cells and lymphocytes. The data showed that targeted therapies have different efficacies towards leukemic AML cells at distinct stages of myeloid differentiation. Particularly, BCL2 inhibitor venetoclax was toxic to immature blasts but was not effective against more differentiated monocytic and granulopoietic cells. In conclusion, we identified novel STAT5B mutations in two rare lymphoproliferative diseases, T-ALL and LGL leukemia. Furthermore, we demonstrate that our ex vivo flow cytometry-based drug screening platform can increase the functional understanding of drug effects.
Originalspråkengelska
UtgivningsortHelsinki
Förlag
Tryckta ISBN978-951-51-4448-5
Elektroniska ISBN978-951-51-4449-2
StatusPublicerad - 2018
MoE-publikationstypG5 Doktorsavhandling (artikel)

Bibliografisk information

M1 - 88 s. + liitteet

Vetenskapsgrenar

  • 3122 Cancersjukdomar
  • 1184 Genetik, utvecklingsbiologi, fysiologi
  • 3111 Biomedicinska vetenskaper

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