Gfi1b as a critical regulator of leukemic stem cells

• Applicant: Professor Dr. Cyrus Khandanpour
• Subject Area: Hematology, Oncology
• Term: from 2014 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249641333

Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic system, which is characterized by an accumulation of immature myeloid blasts. Despite numerous advances in research only 20-30% of all AML patients can be cured. The myelodysplastic syndrome (MDS) is a premalignant disease of the bone marrow in which the differentiation of various hematopoietic lines is disturbed. A part of the patients suffering from MDS can develop AML. Similar to the normal hematopoietic system, the AML and MDS have a hierarchical structure of the affected cells. So-called leukemic stem cells (LSC) give rise to blasts that are characteristic for the disease. Gene expression changes as well as mutations of transcription factors play an important role in the development of AML, as shown previously for CEBPA, PU.1 and AML1.Gfi1b is such a transcription factor that controls the differentiation of various hematopoietic lines. We could previously show that Gfi1b inhibits the expansion of stem and precursor cells.During the first funding period we could demonstrate thatI. Reduced expression of GFI1b in blast cells of MDS and AML patients is associated with an inferior prognosis of MDS ad AML patientsII. Loss of Gfi1b accelerates AML development in different murine models of human AML.III. Loss of Gfi1b increases number of functional murine LSC.IV. Loss of Gfi1b leads to epigenetic changes contributing to AML development. V. Loss of Gfi1b in leukemic stem cells leads to deregulation of the ROS/p38 signal cascade.VI. Loss of Gfi1b is associated with deregulation of Mapk/p38/Foxo3 cascade, which in turn leads to an altered metabolic state of a leukemic cellVII. We have hints, that loss of Gfi1b leads to increased oxidative phosphorylation of leukemic cells. Other groups have shown that increased oxidative phosphorylation is associated with increased resistance of leukemic cells towards chemotherapy. Hence this could potentially explain, why AML patients with low GFI1b expression in their AML blasts have a poor prognosis. However, more work is needed to decipher the exact mechanism how loss of Gfi1b contributes to AML development on a metabolic stage and whether this can be exploited for novel therapeutic approaches. Specifically we want to:1) Using the PiggyBac mouse model, we want to decipher with which mutations of different signaling cascades loss of Gfi1b cooperates to induce leukemia2) Decipher whether loss of Gfi1b affects metabolic state of a leukemic cell 3) Explore whether the altered meatobolic state of a leukemic cell leads to different epigenetic status of the leukemic cells4) Whether the altered metabolic state of Gfi1b low expressing leukemic cells can be exploited on a therapeutic level.The grant would allow us developing potentially novel, chemofree approaches to treat patients with low/absent expression of Gfi1b/GFI1B.

• DFG Programme: Research Grants