Forsøksdyr: Role of inflammation in MLL-AF9 acute myeloid leukemia (transfer to Tromsø)


Godkjenningsdato 01.09.2020

Godkjenningsperiode 01.09.2020-31.12.2022

The aim of this project is to study the contribution of inflammation in acute myeloid leukemia (AML) development and progression, and to investigate possible treatments. Results will lead to advances in AML knowledge and patient treatment improvement. C57BL/6 and Nes-GFP mice will be used as recipient of MLL-AF9 knock in (MLL-AF9 HE) and control (MLL-AF9 WT) bone marrow (BM) cells (n=610 in total- 450 in Tromsø and 160 in Oslo). Nes-GFP mice will allow us to study the bone marrow microenviroment in through trace of nestin+ cells. Prior to transplantation, recipient mice need to be myeloablated through whole body irradiation. Total whole body irradiation is used in the field of blood stem cell function and cancer (for more information: http://www.bu.edu/orccommittees/iacuc/policies-and-guidelines/irradiation-of-rodents/). It allows to kill proliferating blood cells without significant damage of resting tissues, and simultaneously promotes proliferation of transplanted cells. Mice might not feel well for the first 7-14 days and may lose up to 26% of their body weight, which after transplant, will be mostly regained by Day 14-21 post-irradiation. Animals should be on their way to recovery at day 21 (cut-off weight loss 15%), and recovered at day 30 (cut-off weight loss 10%). All mice will be transplanted after irradiation. Inflammation/anti-inflammation will be controlled by treatment with low doses of several drugs. Some mice will be treated with anti-inflammatory drugs together with conventional chemotherapy: 5 daily doses of cytarabine (100mg/kg) + 3 daily doses of doxorubicin (3mg/kg) (Sanchez Aguilera et al, 2014). Chemotherapy is a common treatment in cancer. Chemotherapy kills mainly malignant cells which are usually the most proliferative. Chemotherapy exposure induces multiple signs of illness, including lethargy, hunched posture, rough coat, and weight loss. Measurable weight loss occurs immediately after treatment initiation. Mice will be sick after the administration of chemotherapy, and may lose 26% of their weight. A nadir is reached between days 8 and 10, with a gradual recovery to near starting levels within 2 to 3 weeks, and also it may induce regression of the leukemia or prevent its development (Lombardo and Nichols, 2009; Wunderlich et al, 2013). The results will provide a novel platform for more efficient therapies against AML, one of the most aggressive and frequent blood disorders that affects adults and children. It is not the goal of this study to analyze terminal or moribund stages. The irradiation will be performed in two half doses to reduce the adverse effects. Chemotherapy will be standard in the field of hematopoiesis. Study of the contribution of the inflammatory properties of the bone microenvironment can only be studied in vivo. The number of animals will be kept in the minimum necessary to obtain statistically meaningful results, using them in the most efficient way possible.