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Research unit director
Projects

Targeting the progression of myelodysplastic syndrome to acute myeloid leukemia I Role of Gfi1b in the formation of platelets and inherited bleeding disorders I Function of the BTB/POZ domain transcription factor Miz-1 in the activation of lymphoid cells and in lymphoid leukemia and lymphoma I Role of Gfi1 as a modulator of the ATM/DNA-PK DNA damage response pathway

Targeting the progression of myelodysplastic syndrome to acute myeloid leukemia
Funded by the Leukemia and Lymphoma Society

We observed that a subgroup of patients with myelodysplastic syndrome (MDS) carrying a gene variant of the transcriptional repressor GFI1 (GFI136N) is more resistant to treatment with DNA hypomethylating agents and develop a fatal AML much faster than patients carrying the more common GFI136S form. The human GFI1 protein acts as a DNA binding transcription factor that recruits histone modifying enzymes to its target gene promoters genome-wide. We have evidence that the GFI16N variant is defective in mediating these histone modifications and we hypothesize that this deficiency causes the rapid progression of GFI136N positive MDS patients to AML. The objective of the project presented here is to test this hypothesis and to demonstrate how this knowledge can be used to design a novel approach to treat this high-risk subgroup of MDS patients by restoring GFI1 activity. To reach this objective, we have divided our work into three specific aims: Aim 1: Mouse models of MDS to AML disease progression: Determine genome-wide histone methylation and -acetylation levels in leukemic cells from knockin mice that carry the human GFI136S and GFI136N alleles and have progressed from MDS to AML. Aim 2: Samples from human patients with MDS to AML disease progression: Determine genome-wide histone methylation and -acetylation in leukemic cells from AML patients, who carry either the GFI136S or GFI136N alleles and have progressed from MDS to AML. Aim 3: Test of “epigenetic” drugs: Determine the effect of histone methyltransferase and - acetyltransferase inhibitors in GFI136N or GFI136S knockin mice with AML. The results of the study proposed here have a high potential to establish a new rationale to improve current therapies for MDS patients at a high risk to develop AML. In addition, the results of the proposal aim to link aberrant epigenetic modifications to the MDS to AML disease progression. This information will also be essential to design new therapies that enable the reversal of abnormal epigenetic modifications seen in MDS and AML patients.


Role of Gfi1b in the formation of platelets and inherited bleeding disorders
Funded by the Canadian Hemophilia Society (CHS)

Platelets are essential for blood clotting and are formed in the bone marrow by large cells, so-called “megakaryocytes”, which form long protrusions that penetrate into blood vessels, where the shear forces of the blood stream detach small pieces, which form the platelets. Low platelet numbers can be caused by different diseases or can be the result of an inherited disorder that leaves megakaryocytes unable to produce platelets. These heritable diseases are of clinical importance since low platelet numbers can cause excessive bleeding, which can create severe complications for instance during surgery. A better understanding which factors regulate platelet production is therefore needed to develop new treatments for platelets deficiencies. Recently, mutations in a gene called “Gfi1b” have been identified in patients with a bleeding disorder caused by low platelet numbers. We have generated mice deficient for this gene and have observed that they show most of the typical symptoms of the human disease associated with the mutated Gfi1b, suggesting that the Gfi1b gene is a critical element in platelet formation. We propose therefore to investigate how this gene functions and regulates platelet formation to gain new insight how to treat patients with bleeding disorders and platelet deficiencies.


Function of the BTB/POZ domain transcription factor Miz-1 in the activation of lymphoid cells and in lymphoid leukemia and lymphoma
Funded by the Canadian Institutes of Health Research

Lymphoma and leukemia are both cancers of blood cells, blood cell precursors or even blood stem cells that are programmed to form blood cells. While a lymphoma is present as a solid tumor mass in lymph nodes, spleen or thymus, leukemia is characterized by a massive expansion of malignant cells in the bloodstream. Both leukemia and lymphoma are fatal diseases. Therapies exist, but are a heavy burden on patients and in many cases cannot prevent relapse of the disease. In cancer research, one of the major objectives is to render current therapies more efficient and more tolerable to patients. To be able to do this, the molecular mechanisms behind the emergence and maintenance of blood cancers and the intricacies of the cells that form blood cancers have to be known. We have identified a group of three proteins (called Miz-1, c-Myc and Bcl-6), which control the transcription of genes in normal blood cells and their precursors and which seem to be critical for the development of specific types of lymphoma and leukemia. How these proteins work together in blood cells and whether they represent a suitable target structure on which future therapies can be built on is the goal of the present project. We will use mouse models, in which the genes for these proteins can be switched on or off under conditions where lymphoma and leukemia develop. We expect to generate important information that will pinpoint the function of the Miz-1/c-Myc/Bcl-6 complexes and the molecular pathways that they control as a critical element that could be targeted in future therapies against leukemia and lymphoma.


Role of Gfi1 as a modulator of the ATM/DNA-PK DNA damage response pathway
Funded by the Canadian Institutes of Health Research

When cells are subjected to gamma irradiation or certain chemotherapeutic drugs, the chromosomes and in particular the DNA within the chromosomes are damaged. As a consequence, the cells respond by stopping cell division to repair the damage. If the repair is not possible because the damage is too extensive, the cells initiate a self-destruction process called programmed cell death. We have discovered that a particular protein, called Gfi1, which normally regulates gene activity and the packaging of chromosomes in a cell, can modulate the cellular response to DNA damage. Cells that lack Gfi1 overreact to the DNA damage signal and accelerate the initiation of programmed cell death. Of interest, DNA damage is also the underlying cause for the anti-cancer efficacy of ionizing radiation and many chemotherapeutic drugs. Thus, a better understanding of the pathways and regulatory mechanisms of the cellular response to DNA damage is important for making further advances in cancer treatment. In particular, one way to improve cancer therapy would be to selectively sensitize tumor cells to DNA damage inducing drugs or gamma radiation, thus allowing the use of lower doses to effectively cure or control the disease while obviating unwanted side effects. In this project, we intend to clarify the role of the Gfi1 regulatory protein in this process and in the DNA damage response. We propose that in particular blood cells need Gfi1 to counteract a destructive DNA damage response pathway. Our work will clarify which effect the ablation of the Gfi1 protein has in blood cells and whether or how Gfi1 deficiency can sensitize them to an accelerated death. This knowledge can be used for a future therapeutic strategy, in which blood cancer cells (leukemia cells) are sensitized to accelerate their self-destruction during a therapy with chemotherapeutic drugs that cause DNA damage. 

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