“These funds will be instrumental for better stratification of patients and to help predict those that will benefit the most from certain treatments”, Lorena Arranz says.
She is an Associate Professor and Deputy Centre Director at CRESCO, a Center of Excellence (SFF), at the Institute of Clinical Medicine at the University of Oslo.
In 2021, she was awarded 12 million NOK from the Research Council for her project "Exploring the transformation potential of haematopoietic stem cells under niche pressure, and its therapeutic targeting."
The project has been transferred from the University of Tromsø to the University of Oslo in connection with the transfer of her research group and establishment of CRESCO.
How does blood cancer develop?
In the project, Arranz and her team aim to gain more knowledge about how blood cancer develops and what happens in the early stages of disease development.
"The goal is to find new treatment methods that can target these early stages of cancer development. This can contribute to better ways of detecting, treating, and preventing blood cancer," she explains.
By identifying new targets for treatment, the researcher aims to improve survival rates and the quality of life for patients with these diseases.
Imbalance in stem cell development can lead to cancer
The project focuses on the development of two types of blood cancers, Acute Myeloid Leukemia (AML) and Myeloproliferative Neoplasms (MPN).
To find out more on the development of these types of cancers, Arranz and her colleagues will explore the microenvironment around blood stem cells, known as hematopoietic stem cells (HSC), in the bone marrow where the HSC reside.
Stem cells have a unique ability to self-renew through cell division and can differentiate into a variety of different cell types. Blood stem cells, the ones Arranz is researching, give rise to all blood cells in the organism.
"Stem cells have a fascinating ability to ensure tissue regeneration, and to provide the source for replenishing mature cells in the organism throughout its life," says the researcher.
"However, this must be fine-tuned as their imbalance may contribute to negative outcomes such as aging and cancer" she says.
What happens in the microenvironment around blood stem cells?
The stem cell niche plays a crucial role in stem cell behavior.
“We will explore how external signals present in the microenvironment that surround HSC may have the potential to contribute to the malignant transformation of the stem cell”, says Arranz.
“We will also explore how targeting these external signals could be exploited therapeutically, she says.
AML is an aggressive form of cancer
One of the types of blood cancer that they will study is acute myeloid leukemia (AML). It is the most frequent form of acute leukemia occurring in adults.
“AML is highly aggressive, and its prognosis remains poor,” says Arranz.
“Overcoming these problems requires improved understanding of the fundamental processes underlying the origin of the disease”, she says.
Defective control of inflammation can lead to disease progression
In the AML-part of the project, the researchers will focus on a specific protein.
People with AML often have low levels in the body of a protein called interleukin-1 receptor antagonist (IL-1RN). The protein regulates inflammatory responses in the body. Having low levels of IL-1RN gives the body poorer control over inflammation.
“Our previous work with mouse models has shown that defective control of inflammation through low levels of IL-1RN contributes to AML progression”, Arranz explains.
The researchers also found that the expression level of IL-1RN in blood cells is a prognostic marker for poor survival in AML patients.
– Our work further provides a basis for interleukin-1-beta blocking therapeutic potential against this disease, she says.
What are the mechanisms that cause low levels of IL-1RN in AML-patients?
In collaboration with the team of Professor and Center Director Arne Klungland and CRESCO, Arranz wants to explore this further.
“We will now determine the mechanisms that cause the low levels of IL-1RN in many AML patients”, she says.
Using big data sets, she will also study whether these mechanisms correlate with clonal hematopoiesis, a pre-leukemic condition, and thereby predispose to blood cancer and age-related diseases.
Nerve cells in the bone marrow affect blood cancer development
The second part of the project looks at Myeloproliferative Neoplasms (MPN), a group of bone marrow cancers whose major complication is the transformation to AML.
“We have previously shown that neuropathy in the bone marrow is essential for MPN development”, says Arranz.
She and her colleagues, the team of Associate Professor Francisca Ferrer Marin at Hospital Universitario Morales-Meseguer in Spain, have now found enrichment in MPN patients of genetic variants in a specific gene called NTRK1. This gene is important for the survival and growth of nerve cells. There, too, it seems important that the signals function as they are supposed to.
The researchers will now try to understand the functional impact of these genetic variants in the origin of MPN.
New knowledge into the origin of blood cancer diseases
The researchers at CRESCO will therefore investigate how these mechanisms affect the function and properties of blood stem cells.
They will do this by using both samples from patients with these mutations as well as mouse models.
“Our goal is to understand more about how these molecular alterations play a role in the development of MPN and AML, and their potential interactions. Our approach will provide new knowledge into the origin of blood cancers”, Arranz says, and adds:
“This knowledge can contribute to earlier diagnosis and better treatment of these blood cancers in the future”.