Specific MLL partner genes in infant acute lymphoblastic leukaemia (ALL) associated with outcome are linked to age and white blood cell count (WBC) at diagnosis: Children’s Oncology Group (COG) P9407 trial reports

Infants with leukaemia remain one of the most challenging populations to treat in all of paediatric oncology. Leukaemia, of which the most common form in children is acute lymphoblastic leukaemia (ALL), is the most widespread cancer in children and in infants less than one year old. Most infants less than one year old with ALL respond poorly to chemotherapy drugs and have a much lower survival rate than do older children. One factor associated with poor outcomes in infant ALL is the MLL translocation, a molecular abnormality in which the MLL gene on chromosome 11 breaks and then becomes joined with one of a number of different “partner” genes on other chromosomes. In collaboration with the Children’s Oncology Group (COG), researchers from the Children’s Hospital of Philadelphia determined the specific partner genes involved in MLL translocations among cases of ALL in infants enrolled in the clinical trial COG P9407 for the treatment of infant ALL. The researchers then assessed how different MLL partner genes affected outcome and studied how they were related to other classical prognostic factors, including age and white blood cell count at diagnosis. This research was funded by SCOR grant 7372-07 from the Leukaemia & Lymphoma Society.

A total of of 221 infants with ALL were enrolled in the COG P9407 trial. Researchers used several methods (e.g., Southern blot analysis, reverse transcriptase polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), etc.) to identify MLL translocations and specific partner genes at the levels of the genes and chromosomes. Statistical tests were then used to determine how MLL translocations with different partner genes affected the prognosis, and their relationships to classical prognostic factors.

The COG researchers found that the leukaemia cells of 74 percent of infants with ALL had an MLL translocation and that the most common partner genes of MLL were AF4, ENL, and AF9. The two most common partner genes of MLL, AF4 (located on chromosome 4) and ENL (located on chromosome 19), negatively affected patient survival. Better outcomes were observed when the MLL gene fused with AF9, located on chromosome 9. The outcome was far worse when AF4 or ENL occurred as partner genes in MLL translocations in cases of ALL in younger infants who were less than 90 days old at diagnosis. In addition, translocations fusing MLL with AF4 were associated with a higher white count, whereas translocations fusing MLL with AF9 were associated with a lower white blood cell count. These new associations of specific MLL partner genes with age and white blood cell count indicate how disease biology and the classical prognostic factors in infant ALL are integrally connected.

“The ability to characterize acute lymphoblastic leukaemia based on specific partner genes may provide a new way to determine whether infants with ALL in which the partner genes of MLL are different will benefit from specific types of treatment,” said senior study author Carolyn A. Felix, MD, Professor of paediatrics at the Children’s Hospital of Philadelphia. “We hope that these findings will help lead to the development of new, molecularly targeted therapies for infants with leukaemia.”