Long non-coding RNA and inflammation in acute myeloid leukemia: a possible regulatory feedback loop.

Image: By Nia Cason | Freelance scientific writer

Acute myeloid leukemia is the most common form of leukemia. With an estimated global incidence of 3–8.7 people per 100,000, it’s easy to understand the importance of identifying therapeutic targets and reliable diagnostic markers. In new work, Dr Sebastien Chateauvieux of Professor Marc Diederich’s lab found that PTTG1-1:1, a long non-coding RNA, affects survival of patients with acute myeloid leukemia via a feedback loop of the regulation of inflammation.

RNAfold webserver (Picture from LBMCC - Chateauvieux)

Acute myeloid leukemia is a fast-growing cancer that starts in bone marrow before moving to the blood, and primarily develops from cells that are programmed to turn into white blood cells. There is still no effective treatment for many hematological malignancies, largely because the underlying molecular mechanisms are not yet fully understood. We know that an elevated level of tumor necrosis factor (TNF), a protein that causes inflammation, is a bad prognostic factor for survival in acute myeloid leukemia – it can actually promote the growth and survival of cancer cells. By contrast, anti-inflammatory cytokines have been reported to slow disease progression. This tells us that a disturbed balance between pro- and anti-inflammatory mediators could cause proliferation and survival of leukemic cancer cells. But how, exactly? One candidate is the effect of TNF-α onlong noncoding RNA (lncRNA).

Long non-coding RNA and cancer

LncRNAs have more than 200 nucleotides and are non-coding, like microRNAs, which means they do not become translated into proteins – so what’s their biological relevance? Recent work has shown that they regulate both gene expression and protein activity. Recent evidence has also highlighted their roleinvolvement in almost all biological processes, but also including cancer and other immune-mediated diseases. Dysregulation of lncRNAs has been implicated in liver cancer, breast cancer, and colorectal cancer, but there have been conflicting results in acute myeloid leukemia.

An important lncRNA in acute myeloid leukemia: PTTG1-1:1

Using data from the BloodPool AML database, recent work by Dr Sebastien Chateauvieux, Professor Marc Diederich, and their colleagues revealed that a specific lncRNA, PTTG1-1:1, was upregulated by nearly 3-fold in patients with acute myeloid leukemia. Furthermore, higher PTTG1-1:1 levels were associated with a better survival rate. Could this mean that PTTG1-1:1 has a tumor-suppressing action?

Chateauvieux and colleagues examined this question by looking at the effects of over- and under-expression of PTTG1-1:1. Lower levels of PTTG1-1:1 resulted in higher levels of the cancer cell markers CD14 and CD11b. Higher expression of PTTG1-1:1 resulted in a downregulation of CD15, another marker of cancer cells. These results could indicate that lower PTTG1-1:1 levels increase cancer cell proliferation and higher PTTG1-1:1 levels decrease cancer cell proliferation.

What causes these higher levels of PTTG1-1:1 in acute myeloid leukemia?

Diederich’s team found that PTTG1-1:1 was regulated by inflammation; TNF-α-induced inflammation caused an increase in the expression of PTTG1-1:1 in leukemia cell lines and blood cells from patients. The team’s proposed chain of events is that TNF-α induces NF-κB activity (a transcription factor that regulates immune response-related genes), which upregulates PTTG1-1:1. This indicates that the higher levels of PTTG1-1:1 seen in patients with acute myeloid leukemia is a kind of immune response to the higher levels of TNF-α.

Inflammation isn’t good in acute myeloid leukemia, yet it increases PTTG1-1:1 expression, which subsequently improves patients’ prognosis. The researchers therefore highlighted the possibility that PTTG1-1:1 regulates inflammatory processes to avoid over-activation of inflammation, by, for example, interrupting NF-κB signaling. In this way, the PTTG1-1:1 overexpression seen in acute myeloid leukemia might regulate inflammatory mRNA levels to initiate a negative regulation feedback loop. Most importantly, these new findings highlight the important role of lncRNA in the regulation of acute myeloid leukemia-associated inflammatory processes, which improves clinical outcomes.

Long non-coding RNA and inflammation in acute myeloid leukemia: a possible regulatory feedback loop.

Long non-coding RNA and inflammation in acute myeloid leukemia: a possible regulatory feedback loop.

Acute myeloid leukemia is the most common form of leukemia. With an estimated global incidence of 3–8.7 people per 100,00...

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