10 May

Study identifies potential target for treating childhood blood cancer

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Research into a type of blood cancer called juvenile myelomonocytic leukaemia suggests anti-inflammatory treatment as a possible new therapy for the disease. That is what scientists from the group of Jeroen den Hertog have concluded in a study with zebrafish, published in eLife on the 10th of May.

The scientists have pinpointed a possible new target for treating patients with the blood cancer juvenile myelomonocytic leukaemia (JMML). Their findings in zebrafish and JMML patients suggest that treatment using anti-inflammatories could be a possible new approach to combating the disease.

JMML is a highly aggressive blood cancer with poor outcomes for patients. Children with a relatively common developmental syndrome called Noonan Syndrome have a high risk of developing a condition similar to JMML, called myeloproliferative neoplasm, which can then progress to JMML. The most frequent genetic cause of JMML and NS is a mutation in the PTPN11 gene, which encodes the protein-tyrosine phosphatase SHP2.

“Hematopoietic stem and progenitor cells are considered to be the cells of origin for JMML,” says first author Maja Solman. “Currently, hematopoietic stem cell transplantation is the only treatment for the disease, but it has a relapse rate of 50%. With such limited treatment options for JMML, we wanted to gain a better understanding of how the disease develops to identify other possible ways of targeting it.”

To do this, Solman and the team used a novel zebrafish model with a mutation in SHP2 – equivalent to the most common mutation in NS patients which can cause JMML. They used a technique called single-cell transcriptomics to examine the level of gene expression in the animals’ hematopoietic stem and progenitor cells. The analysis showed an increase in the number of monocyte and macrophage progenitor cells in the fish embryos, and that these cells expressed genes associated with the immune response.

This image shows the macrophages and neutrophils in a zebrafish embryo with a mutation in SHP2. The head of the embryo is on the left, the tail on the right. Similar to the situation in JMML patients, this fish has more macrophages and neutrophils compared to fish without a mutation in SHP2. Image credit: Maja Solman
This image shows the macrophages (red) and neutrophils (green) in a zebrafish embryo with a mutation in SHP2. The head of the embryo is on the left, the tail on the right. Similar to the situation in JMML patients, this fish has more macrophages and neutrophils compared to fish without a mutation in SHP2. Image credit: Maja Solman (CC BY 4.0).

The team next compared these results with their analysis of hematopoietic stem and progenitor cells, which contained SHP2 mutations, from the bone marrow of JMML patients. They found a similar pattern of proinflammatory gene expression in these cells as the one they identified in the zebrafish.

Finally, they treated the zebrafish embryos with an anti-inflammatory drug called dexamethasone. They found that the drug helped rescue JMML-like blood defects in the fish, suggesting that anti-inflammatories could one day be an important treatment strategy for JMML.

“Our work reveals striking similarities in the proinflammatory response of human and zebrafish cells containing SHP2 mutations, and shows that inhibiting this response can improve JMML-like symptoms in a zebrafish model,” concludes senior author Jeroen den Hertog. “Together, these findings lay the groundwork for future studies to verify the effectiveness of anti-inflammatories as a potential new treatment approach for JMML patients.”

Publication
Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects. Maja Solman, Sasja Blokzijl-Franke, Florian Piques, Chuan Yan, Qiqi Yang, Marion Strullu, Sarah M Kamel, Pakize Ak, Jeroen Bakkers, David M Langenau, Helene Cave, Jeroen den Hertog. eLife 2022.

Picture Jeroen den Hertog

 

 

Jeroen den Hertog is group leader and managing director at the Hubrecht Institute and professor of Molecular Developmental Zoology at Leiden University.