The role of bone marrow stromal cells in therapy resistance of FLT3-ITD positive acute myeloid leukemia cells
(2021) MOBN03 20182Degree Projects in Molecular Biology
- Abstract
- Activating mutations of the FLT3 receptors confers poor prognosis while remaining as one of the most common causes for the survival and propagation of these leukemic blast cells. Years of research into second generation inhibitors proved to be initially effective. However, current studies suggest that microenvironment-mediated signals from bone marrow stromal cells are capable of providing cytoprotective capabilities in vitro when in co-culture with FLT-ITD against FLT3 inhibitors. This could in turn lead to restoration of inhibited downstream signalling of RAS/MAPK, P13K and Stat5, or by activating alternative downstream pathways, which ultimately could rescue leukemic cells from FLT3 inhibitors. In this study we measure two different... (More)
- Activating mutations of the FLT3 receptors confers poor prognosis while remaining as one of the most common causes for the survival and propagation of these leukemic blast cells. Years of research into second generation inhibitors proved to be initially effective. However, current studies suggest that microenvironment-mediated signals from bone marrow stromal cells are capable of providing cytoprotective capabilities in vitro when in co-culture with FLT-ITD against FLT3 inhibitors. This could in turn lead to restoration of inhibited downstream signalling of RAS/MAPK, P13K and Stat5, or by activating alternative downstream pathways, which ultimately could rescue leukemic cells from FLT3 inhibitors. In this study we measure two different cell lines, MOLM-13 and MV4-11, against five different FLT-3 inhibitors, AC-220, AZD3463, Crenolanib, Sorafenib and PKC-412, while being subjected to HS-5 conditioned medium, a cell originating from the human bone marrow stroma. Here we show that HS-5 is capable at restoring leukemic growth, inhibit FLT3 inhibitor-induced apoptosis, and restoring colony formation from FLT3 inhibition. (Less)
- Popular Abstract
- HS-5: A mysterious fluid cancerous cells can live and breathe in
Cancer can be divided into a myriad of different types depending on their origin and mutation. To understand this diverse disease, we must look into each cancer type among thousands to design a unique medication for each and every kind. And examine every little different case of cancer. This is a story of one of these little cases, whereby a subgroup within a subgroup of cancer, but still a very lethal one, is among the blood cancer types. Relating to early forms of blood cells originating from bone marrow stem cells. This niche of cells exists in the space within the safe and nutritious bone marrow, where new blood cells can grow and emerge. The perfect place for a blood... (More) - HS-5: A mysterious fluid cancerous cells can live and breathe in
Cancer can be divided into a myriad of different types depending on their origin and mutation. To understand this diverse disease, we must look into each cancer type among thousands to design a unique medication for each and every kind. And examine every little different case of cancer. This is a story of one of these little cases, whereby a subgroup within a subgroup of cancer, but still a very lethal one, is among the blood cancer types. Relating to early forms of blood cells originating from bone marrow stem cells. This niche of cells exists in the space within the safe and nutritious bone marrow, where new blood cells can grow and emerge. The perfect place for a blood cancer cell to start a new career or leukemic cells as they are called.
The type of cancer emerging from this place can be further divided into two main lineages, myeloid and lymphoid cell lines. They are responsible of different mechanisms in our immune system. What research has shown successively during the last 20 years is the dependence of leukemic cells on its microenvironment, the space close to them, for survival and growth. Residing within the enclosed microenvironment space, human stromal cells or specifically a type called “HS-5” as it has been designated in our experiment, produces a bountiful supply of important signalling molecules. Some of which are called complex names such as, granulocyte colony-stimulating factor (G-CSF), Kit ligand (KL) or interleukin-6 (IL-6). Many which are necessary for the process known as haematopoiesis, the development of immature stem cells to mature blood cells. Taken together, these molecules persist within the microenvironment which the bone marrow is partially composed of.
By hijacking these signalling and growth molecules, secreted from the human stromal cells inside the microenvironment, leukemic cancerous cells starting their career can multiply to a greater degree by taking advantage of this. One of the advantages is the ability of the microenvironment to “protect” the leukemic cells from programmed cellular death, or halting their growth and survival, from various cancer drugs, designed to kill and suppress these cells.
Certain groups of cancer drugs target specific receptors on cells. Receptors are proteins which can reside on the surface of cells, and other places, that function by transmitting signals between the outside and inside of the cell. One type of receptors is called the FMS-like tyrosine kinase or FLT3, involved in communicating and controlling the growth of blood cells in their earlier stages while they are developing in the bone marrow. Mutations within these FLT3 receptors can cause these blood cells to descend into becoming cancerous by causing uncontrolled growth and survival, triggering these cells to stop listening to the other healthy cells. By understanding how the HS-5 microenvironment helps these leukemic cells, we will be better equipped at ensuring the efficiency of cancer drugs. (Less)
Please use this url to cite or link to this publication:
http://lup.lub.lu.se/student-papers/record/9069235
- author
- Kronqvist, Felix
- supervisor
-
- Kazi Uddin LU
- organization
- course
- MOBN03 20182
- year
- 2021
- type
- H2 - Master's Degree (Two Years)
- subject
- language
- English
- id
- 9069235
- date added to LUP
- 2021-12-17 14:28:00
- date last changed
- 2021-12-17 14:28:00
@misc{9069235,
abstract = {{Activating mutations of the FLT3 receptors confers poor prognosis while remaining as one of the most common causes for the survival and propagation of these leukemic blast cells. Years of research into second generation inhibitors proved to be initially effective. However, current studies suggest that microenvironment-mediated signals from bone marrow stromal cells are capable of providing cytoprotective capabilities in vitro when in co-culture with FLT-ITD against FLT3 inhibitors. This could in turn lead to restoration of inhibited downstream signalling of RAS/MAPK, P13K and Stat5, or by activating alternative downstream pathways, which ultimately could rescue leukemic cells from FLT3 inhibitors. In this study we measure two different cell lines, MOLM-13 and MV4-11, against five different FLT-3 inhibitors, AC-220, AZD3463, Crenolanib, Sorafenib and PKC-412, while being subjected to HS-5 conditioned medium, a cell originating from the human bone marrow stroma. Here we show that HS-5 is capable at restoring leukemic growth, inhibit FLT3 inhibitor-induced apoptosis, and restoring colony formation from FLT3 inhibition.}},
author = {{Kronqvist, Felix}},
language = {{eng}},
note = {{Student Paper}},
title = {{The role of bone marrow stromal cells in therapy resistance of FLT3-ITD positive acute myeloid leukemia cells}},
year = {{2021}},
}