Impact of Chronic Inflammation on the Evolution of Myelodysplastic Syndromes to Leukemia

Author: Pratham Sarkar

Myelodysplastic Syndromes (MDS) are a group of disorders that affect the bone marrow's ability to produce healthy blood cells. MDS typically affects older individuals and is often characterized by an increased risk of transforming into acute myeloid leukemia (AML). Chronic inflammation is a key factor in the progression of MDS to AML.

What is Chronic inflammation?

Inflammation is the body’s defense mechanism against injuries or infections. The immune system releases cytokines and other inflammatory molecules to fight against pathogens. But if the inflammation becomes chronic, it can harm tissues and lead to genetic changes, which raises the chances of developing cancer.

Chronic inflammation is linked to various diseases, including cancer. This ongoing inflammation can create an environment that leads to genetic instability within cells. Over time, this instability increases the likelihood of changes occurring in tissues, which can potentially develop into cancerous growths. One area particularly vulnerable to this process is the bone marrow, where these changes can have serious consequences.

Chronic Inflammation and MDS

In MDS, the bone marrow cannot produce sufficient functioning blood cells because of abnormal hematopoietic stem cells (HSCs). Mutations in genes associated with clonal hematopoiesis (CHIP) and myeloid malignancies, such as TET2 and DNMT3A, make HSCs more vulnerable to mutations. Chronic Inflammation adds to this by exerting oxidative stress and also induces epigenetic modifications, such as DNA methylation and histone modifications which change the gene expression of HSCs. As time progresses, these damaged HSCs gain genetic mutations. 

Credits: BioLamina

Recent studies also show that inflammatory cytokines, like tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), are seen at elevated levels in MDS patients. Such cytokines induce apoptosis (cell death) in normal HSCs allowing for the mutated ones to flourish in the bone marrow. This microenvironment is what accelerates the progression of MDS to AML.

Single-cell RNA sequencing (scRNA-seq) has been vital in identifying previously unknown cell populations in MDS, including abnormal HSCs, helping to understand the cellular changes causing MDS progression.

However, despite these insights, there are challenges in analyzing these complex datasets due to nonlinearity and limitations in deconvolution methods

( computational technique used to separate mixed signals or data into their individual components or cell types). While these methods help identify cell-type-specific gene expression patterns, their accuracy can still be affected by the similarities between cell types of different cells.

Ongoing improvements in computational techniques and deconvolution methods are slowly allowing clinicians to extract meaningful information from complex RNA-seq datasets.

Credits: National Center for Biotechnology Information

Therapeutic Implications

Targeting chronic inflammation can offer new therapeutic treatments for preventing this progression of MDS to AML. Anti-inflammatory drugs, like TNF-α inhibitors, have shown positive results in reducing inflammation. Clinical trials are also trying to combine anti-inflammatory treatments with standard therapies to slow the progression.

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