Finding the origins of infant leukaemia

October 15, 2012
Finding the origins of infant leukaemia
Credit: Thinkstock

Leukaemia arises as a result of genetic or epigenetic alterations in blood cells, leading to an aberrant accumulation of undifferentiated blasts. Understanding the molecular pathogenesis and aetiology of infant leukaemia induced by the MLL-AF4 fusion gene was the subject of the Leukaemogenesis project.

The mixed lineage leukaemia (MLL) gene is one of the most frequently mutated genes in infant acute leukaemias, leading to fusions that involve more than 50 different partners. Detection of MLL translocations at diagnosis is a strong negative of the disease.

In infant acute lymphoblastic leukaemia (ALL), MLL-AF4 is very common and arises in utero. However, very little is known about the nature of the that becomes transformed in the embryo and the mechanisms accounting for its B cell lineage affiliation.

Although various murine models for MLL leukaemias exist, they fail to replicate many of the features of the human disease, suggesting that there are essential steps during early human development required for leukaemia onset. Seeking to address this issue, the EU Leukaemogenesis project was designed to determine the that was most vulnerable to transformation by the MLL-AF4 gene.

As a first approach, scientists explored the in vitro and in vivo developmental impact of MLL-AF4 expression on haematopoietic stem progenitor cells (HSPCs) isolated from umbilical cord blood. MLL-AF4 seemed to augment the proliferation, clonogenic potential and in vivo multilineage haematopoietic engraftment of HSPCs. However, it was not sufficient to induce leukaemogenesis on its own, indicating that either additional hits were required to develop leukaemia or these cells were the inappropriate target.

In a similar way, MLL-AF4 expression was not sufficient to transform haematopoietic cells differentiated from human (hESC). Interestingly, a reduced production of haematopoietic cells was observed concomitant with an enhanced mature endothelial cell fate, suggesting that MLL-AF4 skewed the potential of common haemato-endothelial precursors towards a pronounced endothelial cell fate.

Scientists are hopeful that the precise mechanism of MLL-AF4–mediated cell transformation would be addressed by studying induced pluripotent stem cells (iPSCs) from infant patient blasts. Nonetheless, the platform generated during the Leukaemogenesis project constitutes an important tool for studying cellular and molecular mechanisms during early embryonic development and could be further utilised for drug screening and toxicity.

Related Stories

Recommended for you

New treatment options for a fatal leukemia

July 27, 2015

In industrialized countries like in Europe, acute lymphoblastic leukemia is the most common form of cancer in children. An international research consortium lead by pediatric oncologists from the Universities of Zurich and ...

Modified DNA building blocks are cancer's Achilles heel

July 22, 2015

In studying how cells recycle the building blocks of DNA, Ludwig Cancer Research scientists have discovered a potential therapeutic strategy for cancer. They found that normal cells have highly selective mechanisms to ensure ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.