A new review has identified a probable focus on for treating juvenile myelomonocytic leukemia, a highly intense blood cancer.

Exploration into a form of blood most cancers known as juvenile myelomonocytic leukemia implies anti-inflammatory treatment as a probable new therapy for the sickness

Juvenile myelomonocytic leukemia (JMML) is most prevalent in youngsters less than the age of four. 10% of all conditions come about in newborns less than the age of a few months. Every yr, one particular to two little ones out of a million are identified with JMML. The condition accounts for approximately 1.6 per cent of all blood-associated cancers. It is extra prevalent in males, with boys currently being almost two times as possible as ladies to create JMML.

The correct fundamental leads to of JMML are unclear, nonetheless, practically all sufferers will have a mutation in a RAS gene or a gene that affects the activation stages of Ras proteins that modifies the

JMML is a highly aggressive blood cancer with poor patient outcomes. Children with Noonan Disease (NS), a relatively common developmental syndrome, are at a high risk of having a disorder similar to JMML called myeloproliferative neoplasm, which may later progress to JMML. A mutation in the PTPN11 gene, which encodes the protein-tyrosine phosphatase SHP2, is the most common genetic cause of JMML and NS.

“Hematopoietic stem and progenitor cells are considered to be the cells of origin for JMML,” says first author Maja Solman, Postdoctoral Fellow at the Hubrecht Institute, Utrecht, Netherlands. “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.”

Macrophages and Neutrophils Zebrafish

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. Credit: Maja Solman

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.

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 to 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, Group Leader and Managing Director at the Hubrecht Institute, and Professor of Molecular Developmental Zoology at Leiden University, Netherlands. “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.”

Reference: “Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects” by Maja Solman, Sasja Blokzijl-Franke, Florian Piques, Chuan Yan, Qiqi Yang, Marion Strullu, Sarah M Kamel, Pakize Ak, Jeroen Bakkers, David M Langenau, Hélène Cavé and Jeroen den Hertog, 10 May 2022, eLife
DOI: 10.7554/eLife.73040