Finding the origins of infant leukaemia

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

Tracking the molecular pathway to mixed-lineage leukemia

date Dec 15, 2008

Infants and adults with the blood cancer mixed-lineage leukemia (MLL) typically have a poor prognosis, and most infants die before their first birthdays. Although there are varying causes of MLL, most cases are caused by ...

Unique role for blood formation gene identified

date Sep 12, 2007

All blood cell production in adults depends on the steady work of a vital gene that if lost results in early bone marrow failure, Dartmouth Medical School cancer geneticists have found. Their research reveals an unexpected ...

Recommended for you

Study finds new potential melanoma drug target

date May 02, 2015

A new treatment for melanoma could be on the horizon, thanks to a finding by a UNC Lineberger Comprehensive Cancer Center-led team. In the study, which was published online today in the journal Clinical Ca ...

Surgery for terminal cancer patients still common

date May 02, 2015

The number of surgeries performed on terminally ill cancer patients has not dropped in recent years, despite more attention to the importance of less invasive care for these patients to relieve symptoms and ...

Study provides comprehensive look at brain cancer treatments

date May 01, 2015

Led by the Translational Genomics Research Institute (TGen) and UC San Francisco (UCSF), a comprehensive genetic review of treatment strategies for glioblastoma brain tumors was published today in the Oxford University Press ...

How artificial tanning can lead to melanoma

date May 01, 2015

Young women may be up on the latest fashions and trends as they prepare for prom season. But what many don't know is that the tan that looks oh-so-good with their dress may be the first step toward skin cancer.

User 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.