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Microenvironment a main driver of aggressive multi-lineage leukemia disease type
Date:6/9/2008

s they focused on the most common fusion partner in MLL, a gene called AF9. Previous research showed patients with MLL-AF9 fusions almost exclusively get AML, have an intermediate to poor prognosis, and that leukemia expressing MLL-AF9 is considered a more aggressive disease resistant to chemotherapy.

Although MLL-AF9 fusion is most commonly associated with AML in people, it is occasionally found in ALL as well. Dr. Mulloy's team programmed human umbilical cord blood cells to express MLL-AF9, resulting in diverse leukemia stem cells capable of transforming into either AML or ALL. The researchers influenced the transformation by altering the growth factor proteins that stimulate the differentiation and growth of blood cells, demonstrating how environmental conditions play a critical role in promoting leukemia progression and deciding disease type.

The researchers then built on this finding by adjusting the cell culture microenvironment to transform lymphoid cells into myeloid cells, as well as myeloid cells into lymphoid, highlighting the adaptability of the leukemia stem cell in mixed lineage leukemia.

"Our findings underscored that while some leukemia stem cells in MLL are diverse and able to transform into different lineages, others remain committed to a single disease type," Dr. Mulloy explained. "This information, and our ability to successfully develop human-based MLL models in mice, will be very useful in finding further insights into the early molecular events behind poor prognosis in mixed lineage leukemia."

Researchers also experimented with inducing AML or ALL in mice by using the MLL-AF9-expressing human cord blood cells. Although mouse models have been successful for studying leukemia stem cells in MLL-associated AML, their usefulness is considered limited for modeling the lymphocytic and mixed myeloid/lymphoid forms of the disease. The research team overcame this limitation by transplanting human MLL-AF9-expressing
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Contact: Nick Miller
nicholas.miller@cchmc.org
513-803-6035
Cincinnati Children's Hospital Medical Center
Source:Eurekalert

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