Origins and Genetics Associated With Mixed-Phenotype Acute Leukemia
Investigators have unraveled the origins and identified mutations associated with mixed-phenotype acute leukemia. The study, published by Alexander et al in Nature, potentially lays the foundation for more effective treatment of patients with this high-risk cancer.
Mixed-phenotype acute leukemia is a subtype of acute leukemia that accounts for about 3% of the estimated 3,500 pediatric cases of acute leukemia diagnosed annually in the United States, but it also occurs in adults. Treatment is complicated because mixed-phenotype acute leukemia does not fit cleanly into a single diagnosis but includes features of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). These markers, which help determine treatment, sometimes change with time or treatment, in some cases enough to change the diagnosis from mixed-phenotype acute leukemia to AML or vice versa.
Long-term survival for young patients with mixed-phenotype acute leukemia is 47% to 75%, compared with more than 90% for young patients with ALL and 65% to 75% for those with AML.
“ALL and AML have very different treatments. But [mixed-phenotype acute leukemia] has features of both, so the question of how best to treat patients with [mixed-phenotype acute leukemia] has been challenging the leukemia community worldwide—and long-term survival of patients has been poor,” said Charles Mullighan, MBBS, MD, a member of the St. Jude Children’s Research Hospital Department of Pathology and a corresponding author of the study.
The findings stem from what is likely the most comprehensive genomic analysis yet of mixed-phenotype acute leukemia. Investigators used next-generation sequencing—including whole-genome, whole-exome, and RNA sequencing—to analyze 115 leukemia samples from pediatric patients with mixed-phenotype acute leukemia. Research centers and other organizations in the United States, Europe, Israel, Asia, and Australia provided the samples.
Mutations in Mixed-Phenotype Acute Leukemia
Four subtypes of mixed-phenotype acute leukemia had been previously identified, but until this study, the genetic basis of the T/myeloid and B/myeloid subtypes was a mystery.
Researchers showed that T/myeloid and B/myeloid subtypes are genetically distinct but have similarities to other leukemia subtypes. For example, WT1 was the most frequently mutated transcription factor gene in T/myeloid mixed-phenotype acute leukemia. WT1 is also commonly altered in a subtype of ALL called early T-cell precursor ALL. Researchers took a closer look and found early T-cell precursor ALL and T/myeloid mixed-phenotype acute leukemia shared other molecular similarities and may benefit from similar treatments, including therapies that target cell signaling pathways.
In contrast, 48% of B/myeloid mixed-phenotype acute leukemia cases carried rearrangements in the transcription factor gene ZNF384. The gene rearrangement has also been reported in cases of B-ALL. When researchers took a closer molecular look at cases of B-ALL and B/myeloid mixed-phenotype acute leukemia with ZNF384 rearrangements, they found the diseases were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan explained. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype and the alteration should be used to guide treatment.”
More Research Findings
Investigators also reported evidence that some patients with mixed-phenotype acute leukemia may benefit from existing targeted therapies, including inhibitors that target the tyrosine kinase FLT3. The enzyme drives leukemic cell growth.
Additionally, the scientists showed the mutations were present in developmentally “immature” blood cells, including hematopoietic stem cells. The finding helps resolve an unexplained hallmark of [mixed-phenotype acute leukemia]—why leukemic cells have both myeloid and lymphoid features. In contrast, ALL and AML involve a single type of either myeloid or lymphoid blood cell.
“These findings suggest that the founding mutation occurs early in blood cell development…,” said Thomas Alexander, MD, formerly of St. Jude and now of the University of North Carolina at Chapel Hill.
Researchers used single-cell sequencing techniques to trace mutations to hematopoietic stem cells in a patient with the T/myeloid mixed-phenotype acute leukemia subtype and a patient with the M/myeloid mixed-phenotype acute leukemia subtype. The patients had different genetic alterations. More broadly, the research adds evidence from cancer genetics to support a model of blood system development in which the destiny of progenitor cells is determined later in the developmental process than previously recognized.
Based on the results, researchers have proposed updating the World Health Organization’s classifications of acute leukemia to include three new mixed-phenotype acute leukemia subtypes. They include two subtypes whose signature mutations in the genes WT1 and ZNF384 were identified in this study.
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