Comparative proteomic analysis of adult LMPPs and leukemic cells under stimulation of IFNa

Abstract

Background and objectives: Acute myeloid leukemia (AML) is the most common type of leukemia in adults with relatively high recurrence. Interferon alpha (IFNa) is a type I interferon and it has been shown to have a therapeutic effect on myeloid malignancies in clinical research especially to prevent potentially risky AML recurrence after chemotherapy. Due to the molecular heterogeneity of the disease, the general therapy has limited curative effects. Here, we compare the proteome changes of leukemia cells and normal cells under the immunostimulation of IFNa to discover a more potent therapeutic target.
Methods: The inducible mouse model of MLL-ENL-driven leukemia were used for the experiments. Cells were sorted by FACS. Liquid chromatography and mass spectrometry are applied for DIA (Data-independent acquisition) proteomic analysis.
Results: 1) IFNa stimulated the up-and down-regulation of proteins involved in response to type I IFN and meiosis I in normal cells, 2) IFNa immune response negatively regulated viral process and suppressed the mitochondrial translation in pre-leukemic cells, 3) there are slight differences between ISGs (interferon-stimulated genes) expression in pre-leukemic cells and in normal cells, and MHC class II proteins are differentially expressed in the two cell types, 4) the proteins that are upregulated in pre-leukemic cells but downregulated in normal cells are enriched in many functions
Conclusion: MHC II proteins would not be an effective target for treating AML. Type I IFN stimulation activates inflammatory response but suppresses translation and proliferation in pre-leukemic LMPPs.

Popular Abstract

Leukemia is caused by mutations in some blood cells. However, even the same mutations can result in distinct types of leukemia among different individuals. To find out the effect of interferon-alpha (IFNa) on intrinsic leukemia-initiating cells, our group compared the changes of proteins in normal cells and induced leukemia cells after stimulation with IFNa.
Cancer is a group of devastating diseases. It will occur in many parts of the human body, such as the stomach, skin, and even the blood. Malignant growth of cells during the production of blood in the body will lead to blood cancer. One form of blood cancer is known as leukemia. Leukemia usually arises from a genetic mutation. The genetic mutation is just like screws changed or lost in a machine, and because of this, the machine cannot operate normally, which will lead to the overproduction of blood cells. The terrifying aspect of leukemia is that it is getting worse rapidly. There are many different types of leukemia, and their prevalence varies among populations. Acute lymphocytic leukemia is the most common kind of leukemia, with most acute myeloid leukemia cases in adults. Prompt and effective treatment usually prolongs patients’ lives.
Nowadays, chemotherapy is the primary treatment for leukemia. It will kill leukemia cells efficiently but also kill normal cells. Thus, there are many side effects like fatigue, hair loss, mouth sores, loss of appetite, nausea, etc. With such a lack of specificity, we investigated if we could find some targets that allow the drug to selectively attack the cells in the body without affecting any normal cells. The answer is probably yes. One of the most exciting findings is that some proteins were specifically expressed in normal cells or leukemia cells, for example, some MHC class II proteins. These groups of proteins were not detected in leukemia cells. MHC proteins are a group of proteins that recognise and display foreign substances for immune cells to kill them. The loss of MHC class II proteins in leukemic cells indicates that these proteins should be avoided as therapeutic targets. IFNa is a common protein that can impact tumor cells. The curious thing that we did not expect is that there are more upregulated proteins than downregulated proteins after IFNa stimulation, while without stimulation the numbers of up-and down-regulated proteins are quite even.
Generally, through this work, more potential candidates could be identified and new treatments for adult leukemia can be discovered. Hopefully, it will improve the prognosis and extend patients’ lives when applied in the clinic.

• author: Chen, Yanan
• supervisor: Jenny Hansson
• organization: Department of Immunotechnology; Educational programmes, LTH
• course: KIMM01 20231
• year: 2023
• type: H2 - Master's Degree (Two Years)
• subject: Biology and Life Sciences
• keywords: Leukemia, Acute myeloid leukemia, Interferon-alpha, Proteomics, Hematopoiesis
• language: English
• id: 9135125
• date added to LUP: 2023-08-29 16:24:03
• date last changed: 2023-08-29 16:24:03