Photo by Vera Kratochvil
Infants who have acute lymphoblastic leukemia (ALL) with MLL rearrangements have few other mutations, according to new research.
The findings suggest that targeting MLL rearrangements in these patients is likely the key to improving their survival.
“We frequently associate a cancer’s aggressiveness with its mutation rate, but this work indicates that the two don’t always go hand-in-hand,” said Richard K. Wilson, PhD, of the Washington University School of Medicine in St Louis, Missouri.
“Still, our findings provide a new direction for developing more effective treatments for these very young patients.”
Dr Wilson and his colleagues reported their findings in Nature Genetics.
The researchers performed whole-genome, exome, RNA, and targeted DNA sequencing to identify genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement.
The team was surprised to find that, despite being an aggressive leukemia, the MLL-rearranged subtype had among the lowest mutation rates reported for any cancer. The predominant leukemic clone carried a mean of 1.3 non-silent mutations.
“These results show that, to improve survival for patients with this aggressive leukemia, we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors,” said James R. Downing, MD, of St Jude Research Hospital in Memphis, Tennessee. “That will not be easy, but this study found no obvious cooperating mutations to target.”
Almost half of infants with MLL-rearranged ALL (47%) had activating mutations in the kinase-PI3K-RAS signaling pathway. But the mutations were often present in only some of the leukemic cells.
Furthermore, the researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that, at the time of relapse, the cells lacked these mutations.
“The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis,” Dr Downing said.
The researchers also found that older children with MLL-rearranged leukemia had significantly more mutations than infants—a mean of 6.5 mutations per case (P=7.15 × 10−5).
Furthermore, 45% of the older children had mutations in genes that encode epigenetic regulatory proteins. And, aside from MLL, epigenetic regulators were rarely mutated in infants with MLL-rearranged ALL.
“While MLL belongs to a family of genes that encode epigenetic regulatory proteins, there was a striking difference between infants and older children regarding the frequency of mutations in other epigenetic regulatory genes,” said Anna Andersson, PhD, of Lund University in Sweden.
“This observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients,” said Tanja Gruber, MD, PhD, of St Jude.
“Our working hypothesis is that, in infants, the MLL rearrangement occurs in a developing blood cell, a prenatal progenitor cell, which requires fewer additional mutations to fully transform into leukemia. In contrast, in older patients, the MLL rearrangement isn’t enough on its own.”
