Differentiation Therapy of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is characterized by a differentiation block in the myeloid lineages of the hematopoiesis. After the success of the all-trans retinoic acid (ATRA) differentiation therapy which overcomes this differentiation block for AML subtype acute promyelocytic leukemia, attempts have been made to find similar therapies for the remaining subtypes. Differentiation therapy candidate H4 (derived from a library of small natural products) has been shown to induce phenotypic differentiation in both an AML cell line and a primary AML sample. In this study, we show that treatment with H4 increases the sensitivity to IL3, which is a differentiation-promoting cytokine in normal hematopoiesis, by upregulating expression of its receptor. This knowledge can be used to design future differentiation therapies for AML.Potential Future Differentiation Therapy For Acute Myeloid Leukemia Did you know that a small percentage of acute myeloid leukemia cases have a far better survival rate than the rest? This is achieved by inducing maturation of the blood cancer cells that are trapped in an immature state (a process called differentiation therapy) and thereby restoring normal blood cell production. However, only 10% of AML patients can by treated in this way. Here we investigate by which mechanism our candidate H4 induces differentiation and our results suggest that H4 increases sensitivity of the leukemic cells to normal blood cell maturation signal IL-3. Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and is characterized by the accumulation of immature blood cells which ”clog up” the bone marrow and prevent the normal production of blood cells. Patients are generally treated with chemotherapy, which targets all dividing cells in the body and often results in severe side-effects. The treatment effectively kills a majority of the leukemic cells, but is very ineffective when it comes to eradicating the so-called leukemic stem cells (LSCs) which are believed to be driving the disease. This results in a high relapse-frequency and only 1 in 4 patients are still alive five years after receiving the diagnosis. However, AML patients with the subtype acute promyelocytic leukemia (APL) which represents around 10% of AML cases can be successfully treated with all-trans retinoic acid (ATRA) resulting in a survival rate of approximately 80%. Due to a mutation characteristic for APL, treatment with ATRA forces the immature blood cells to mature, which unclogs the bone marrow and allows for normal blood cell production to resume. By forcing the leukemic cells to mature instead of simply killing them off, the LSCs are also forced to mature, thereby losing their ability to cause a relapse. This concept of unlocking the blocked maturation is referred to as ”differentiation therapy” and is especially appealing as it avoids the side effects of cytotoxic chemotherapy by maturing cells instead of killing them. More importantly, it also increases the chance of complete remission. There is therefore great interest in finding similar maturation-enforcing differentiation therapies for the remaining 90% of AML cases. We have identified a candidate molecule (code name ”H4”) that successfully increases cell maturation in AML cell lines and post-relapse patient samples based on what surface markers (tags which indicate group affiliation) the cells express. How H4 interacts with the cells is not currently known, but has been hypothesized to be connected to increased kinase signaling. I have examined which signaling pathways in the cell are involved in the interaction. Results point towards treatment with H4 increasing the cells’ sensitivity to IL-3, a signaling substance which is a signal for maturation in normal blood cell development. This could be one factor in how H4 forces the leukemic cells to mature, and that knowledge can be used to design a future differentiation therapy for AML and improve patient survival rates