The Role of MN1-TEL, MN1 and TEL2 in Leukemia
Blood cells arise from a common totipotent hematopoietic stem cell after sequential differentiative steps in a process termed hematopoiesis. Abnormal proliferation along this process is crucial in the occurrence of leukemias. Understanding the relationships among cells of the hematopoietic system and the mechanisms underlying leukemogenesis constitutes a key priority of modern cancer research. The first goal of this thesis was to clarify the role of TEL2 in hematopoiesis and leukemogenesis. Our data show that TEL2 behaves as a bona fide oncogene in vivo, causing myeloproliferative disease (MPD) in mice. However, development of leukemia upon TEL2 overexpression requires cooperation of secondary mutations. Indeed, expressing TEL2 in Arf-/- bone marrow the onset of disease accelerates and phenotype shifts from MPD to B-cell lymphoma. Most importantly, we show that TEL2 directly regulates mTOR in Arf-/- pro-B cells, and propose a model whereby TEL2-dependent upregulation of mTOR is partly responsible for increased proliferation and survival rates of malignant cells, but must cooperate with additional growth-promoting signals dependent on TEL2 function. The second part of this thesis analyzes the role of MN1-TEL as hematopoietic oncogene, demonstrating its ability to cause myeloid malignance when expressed in murine bone marrow. These studies led us to discover that MN1 can per se stimulate the growth of mouse myeloid progenitors, causing MPD in mice. In addition we show that MN1 is upregulated in inv(16) AML patients, and when expressed in mice it cooperates with Cbfβ-SMMHC (the product of inv(16) rearrangements), leading to AML.
|Keywords||AML, ETS factors, MNI, MNI-TEL, MPD, TEL, TEL2, acute myeloid leukemia, chromosomal transloc actions, hematopoiesis, leukemia, myeloproliferative disorder|
|Promotor||F.G. Grosveld (Frank)|
|Publisher||Erasmus University Rotterdam|
|Sponsor||The studies described in this thesis were performed in the Department of Genetic and Tumor Cell Biology, at St. Jude Children’s Research Hospital, Memphis (TN, U.S.A.), supported by the NCI grant CA72999, the cancer center (CORE) support grant CA217G and the American Lebanese Syrian Associated Charities (ALSAC).|
Carella, C.. (2007, January 31). The Role of MN1-TEL, MN1 and TEL2 in Leukemia. Erasmus University Rotterdam. Retrieved from http://hdl.handle.net/1765/16469