In Poland every year approximately 800 people are diagnosed with acute myeloid leukaemia (AML) [1]. Nearly 1/5 of them receive such a shocking diagnosis by accident, usually during a routine blood morphology [1]. However, let’s stop for a moment and ask the fundamental question: what actually is acute myeloid leukaemia and how it develops?

To start with some background – leukaemia, a cancer of white blood cells causing their uncontrollable growth and reproduction, is classified by the type of blood cells that it affects [2]. The first group involves granulocytes and monocytes, and the second – lymphocytes. Both granulocytes and monocytes derived from myeloid stem cell lineage, which means that during haematopoiesis (formation of blood cellular components) it is a myeloid stem cell that will give a rise to either a granulocyte or a monocyte. Just to make things more complicated, it can also differentiate into an erythrocyte (red blood cell) and platelets but do not worry, we will focus purely on the white blood cells here. When it comes to the lymphocytes, they come from lymphoid progenitor cells. Hematopoiesis takes place in your bone marrow from where blood components are released to a bloodstream, although it can also take place in other parts of your body e.g. spleen or liver. The process starts during an embryonic development and continues throughout adulthood as it is essential to produce and replenish the blood system.

As mentioned, these differences in haematopoiesis allowed scientists to group cancers depending on the type of white blood cells they are affecting such as myeloid leukaemia affecting granulocytes or monocytes and lymphoblastic leukaemia affecting lymphocytes. These leukaemias can be differentiated further into acute or chronic. Simply speaking, acute leukaemias develop quickly and usually require harsh and prompt treatment while chronic leukaemias develop slowly and very often need management over many years. 

In this article, I will be focusing on AML – an aggressive disorder of haematopoietic stem cells and progenitors. Due to this disorder leukocytes are less mature, develop much faster and become dysfunctional once they leave the bone marrow [3]. Very important cell type present during AML are leukaemic stem cells (LSCs) representing a low-frequency subpopulation of leukaemia cells [4]. These incredibly interesting cells possess some stem cell properties like self-renewal capacity (upon cell division, stem cell will renew itself so that a stem cell pull is perpetuated throughout life). Furthermore, they can acquire driver mutations and become treatment resistant. In this scenario, bone marrow and multiple organs can be seriously damaged due to widespread tissue devastation caused by LSCs fueling the over-proliferation of primitive myeloid progenitors.

Searching for the alternative

Current AML therapies are very toxic to normal haematopoiesis and usually fail to fully eliminate LSCs. Cell population that survives the treatment can trigger minimal residual disease (a small number of cancer cells is left in a body after the treatment), ultimately causing fatal disease relapses. Considering all of the sobering survival outcomes, we are in serious need to identify new therapeutic targets for selective LSCs elimination (so that other non leukaemic stem cells will remain intact). Laboratory of prof. Kamil Kranc at the Barts Cancer London faces such an issue by employing multidisciplinary approaches to identify novel therapeutic targets that will allow to eradicate LSCs without perturbing normal HSCs and multilineage haematopoiesis. 

Prof. Kamil Kranc’s research group decided to focus on two main subjects:

–       RNA modifications to eliminate LSCs

–       Hypoxia pathways in normal and malignant haematopoiesis

RNA modifications and their role in AML

Emerging evidence indicates that modification of the mRNA N6-methyladenosine (m6A), which is an important regulator of normal and malignant haematopoiesis, may become potentially crucial in treating AML [5] [6]. The subject is quite convoluted so I will start with some basics. 

Epigenetic modifications are changes made to either DNA or RNA that regulate whether genes are expressed. Importantly, these modifications are stable, heritable and do not alter the nucleic acids sequence [7]. m6A is the most common internal mRNA epigenetic modification that, accompanied by other epigenetic regulatory mechanisms (the epitranscriptome), is a new promising area of intensive investigations in cancer research. 

Seminal discoveries by the prof. Kranc’s group (in collaboration with prof. Donal O’Carroll in Edinburgh) and other laboratories revealed that methylation (addition of a methyl group to RNA) at the N6 position of m6A is an important regulator of LSCs in AML [5] [6]. Knowing that, the laboratory of prof. Kranc aims to therapeutically target the key regulators of m6A and other diverse RNA modifications that will enable LSCs to eradicate solely. Their goal is to harness this knowledge to provide treatments for blood malignancies and other cancers which we are desperately looking for at the moment. 

Hypoxia pathways in haematopoiesis

Both normal and malignant haematopoiesis occur in the hypoxic (low in oxygen) bone marrow microenvironment. What is interesting, the impact of hypoxia and hypoxic signaling pathways on normal HSCs, progenitor fate decisions and leukaemogenesis (the development of leukaemia) remains largely unexplored. The laboratory of prof. Kranc in collaboration with prof. Sir Peter Ratcliffe and Christopher Schofield in Oxford has made an important breakthrough, namely, they discovered that several hypoxia sensing enzymes play crucial roles in LSC biology and AML propagation. Therefore, they aim to develop possible ways to inhibit such enzymes, thus eliminating LSCs. 

The importance of prof. Kranc research

The research conducted by the laboratory of prof. Kranc will undoubtedly reinvent the way by which we perceive AML treatments today. However, considering LSCs as a paradigm for other cancer stem cells, their investigation may also have a broad ramification in other blood malignancies and solid tumours! Not to mention that by researching stem cells, the prof. Kranc’s group may also contribute to the improvement of stem cell therapies that are being developed as treatments for some blood cancers as well as disorders affecting the immune system.

Without a doubt, there is so much potential in the therapeutic targets researched by prof. Kranc’s laboratory. I hope to witness their research transforming into revolutionizing therapies that will restrict the collateral damage caused by many present-day treatments. 

References:

1. Newseria B. In Poland every year there are 800 cases of AML being diagnosed. Patients have access to only one modern medicine [Internet]. 2022. (biznes.newseria.pl). Available from: https://biznes.newseria.pl/news/w-polsce-co-roku,p2001027290

2.     NHS. Acute Myeloid Leukaemia [Internet]. 2022. (www.nhs.uk). Available from: https://www.nhs.uk/conditions/acute-myeloid-leukaemia/

3.     Rees M. Acute vs. chronic leukemia: Comparison [Internet]. 2021. (www.medicalnewstoday.com). Available from: https://www.medicalnewstoday.com/articles/acute-vs-chronic-leukemia

4.     Meng S, Zhou H, Feng Z, Xu Z, Tang Y, Wu M. Epigenetics in Neurodevelopment: Emerging Role of Circular RNA. 2019;13:327. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31379511

5.     Mapperley C, van de Lagemaat LN, Lawson H, Tavosanis A, Paris J, Campos J, et al. The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function. 2021 Mar 1;218(3). Available from: https://www.ncbi.nlm.nih.gov/pubmed/33156926

 6.  Paris J, Morgan M, Campos J, Spencer GJ, Shmakova A, Ivanova I, et al. Targeting the RNA m6A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia. 2019 Jul 3;25(1):137-148.e6. Available from: https://dx.doi.org/10.1016/j.stem.2019.03.021

7.   Hanekamp D, Cloos J, Schuurhuis GJ. Leukemic stem cells: identification and clinical application. 2017;105(5):549–57. Available from: https://link.springer.com/article/10.1007/s12185-017-2221-5

Kamil Kranc

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Kamil R Kranc is a Chair of Haematology (Full Professor) and the Deputy Lead of Centre for Haemato-Oncology at Barts Cancer Institute. Prof. Kranc completed his medical degree at the Medical University of Silesia, Poland (1994-2000), a DPhil (PhD) in Biochemistry at the University of Oxford (2000-2003) and a postdoctoral training at the MRC Human Immunology Unit in Oxford (2003-2007). He was a Junior Principal Investigator at the MRC Molecular Haematology Unit at Oxford (2007-2010), and a Group Leader at the Paul O’Gorman Leukaemia Research Centre at the University of Glasgow (2010-2013). From 2013 to 2018, he was a Professor of Molecular Haematology at the University of Edinburgh. He joined Barts Cancer Institute as a Chair of Haematology in 2018.

Wiktoria Bulik

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A graduate of the University of Bedfordshire in Biomedical Sciences. Strongly passionate about science, entrepreneurship and medical innovations. She adores broadening her knowledge and learning new things. On a daily basis, she works in a bio-tech industry, is socially active and takes part in many interesting projects both in Poland and abroad.