Unveiling the Roots of Deadly Infant Leukemia

Researchers at the Josep Carreras Leukaemia Research Institute have identified the genetic foundation for newborn B-cell Acute Lymphoblastic Leukaemia (B-ALL) glucocorticoid resistance through MLL gene rearrangements.

In a new study, Dr. Belén López-Millán and Dr. Clara Bueno present evidence of complicated interactions between the MLL-AF4 gene fusion and NG2, which result in glucocorticoid receptor suppression and hence promote resistance to conventional therapy.

B-ALL is the most prevalent pediatric malignancy, and owing to a highly successful treatment based on glucocorticoids, 5-year survival rates have risen to 85% or higher. However, there is a B-ALL subtype that is typically detected in newborns (less than one-year-old) and reacts extremely poorly to glucocorticoids; with no other treatment option, its prognosis is terrible, and survival rates remain around 30%.

An MLL gene rearrangement distinguishes this glucocorticoid-resistant B-ALL subtype. This suggests that a DNA fragment containing this gene has relocated elsewhere in the genome due to random genetic cut-and-paste. This is rather frequent in cancer cells, and depending on where the piece is copied, there could be ramifications.

In most cases of B-ALL with MLL rearrangements (MLLr B-ALL), this gene combines with another called AF4, resulting in a novel fusion protein (MLL-AF4) with surprising properties.

A Complex Series of Events

The research team was led by Dr. Belén López-Millán, who is also affiliated with the University of Granada, and Dr. Clara Bueno, along with Drs. Jose Luis Sardina and Biola Javierre from the Josep Carreras Institute, Dr. Juan Ramón Tejedor and Mario Fraga's team from CINN/CSIC – ISPA – IUOPA, and other research teams from Spain, Italy, Germany, and the UK, have produced the characteristic glucocorticoid resistance in MLLr B-ALL and the dismal prognosis of the disease. The study was released in the esteemed journal Blood, which is the main outlet of the American Society of Hematology.

They observed that the MLL-AF4 fusion protein increases the creation of NG2, a protein absent from healthy hematopoietic cells, using cutting-edge genomic and proteomic techniques. This abnormal NG2 synthesis has the effect of interacting with FLT3, a protein that the cell utilizes as a sensor to respond to growth signals throughout development and activate it even in the absence of its particular proliferation signals.

The inactivation of the glucocorticoid receptor, which makes the cell resistant to conventional B-ALL therapy, is one of the hallmarks of cancer that is facilitated by FLT3 activation. The well-known repressor protein AP-1 is the last effector of this inactivation.

Even though the majority of the research was conducted using in vitro and ex vivo techniques (using mice as xenografts), and the results are still in the preclinical stage, these findings are invaluable for clinical research because the more cellular systems that are affected by, the more targets there are for future targeted treatments or immunotherapies.

With this new information, many families could have hope for an alternate treatment for their infants with glucocorticoid-resistant MLLr B-ALL.