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Genomic Analysis Reveals Molecular Features of Mixed Phenotype Acute Leukemia Subtypes

NEW YORK (GenomeWeb) – Researchers from St. Jude Children's Research Hospital, the University of North Carolina at Chapel Hill, and other centers around the world have characterized molecular features in a high-risk leukemia subtype called mixed phenotype acute leukemia (MPAL).

The team used exome sequencing, RNA sequencing, whole-genome sequencing, and/or SNP arrays to profile tumor samples from more than 100 children with MPAL — a disease marked by both myeloid and lymphoid leukemia features. The results, which appeared online today in Nature, revealed molecular differences between T/myeloid and B/myeloid subtypes of MPAL. In particular, the T/myeloid form often contained alterations affecting both copies of the WTI gene, while the B/myeloid MPAL more often harbored ZNF384 rearrangements.

"The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype and the alteration should be used to guide treatment," co-corresponding author Charles Mullighan, a pathology researcher at St. Jude and co-leader of the center's hematological malignancies program, said in a statement.

More broadly, the researchers' analyses suggested that the mixed features found in the MPAL tumors reflect genetic mutations that originally occurred in hematopoietic progenitor cells, which went on to differentiate into varied blood cell types.

As many as 3 percent of childhood acute leukemia cases are classified as MPAL, the team noted, while another form of acute leukemia of ambiguous lineage (ALAL) leukemia called acute undifferentiated leukemia is far more rare. And given the poor outcomes for children or adults diagnosed with MPAL, there is interest in understanding whether the tumors should be treated like the other forms of acute leukemia they resemble, or in another manner.

"[Acute lymphoblastic leukemia] and [acute myeloid leukemia] have very different treatments. But MPAL has features of both," Mullighan said. "So the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide — and long-term survival of patients has been poor."

The researchers began with samples from 159 children with ALAL, including 49 with T/myeloid MPAL, 35 with B/myeloid MPAL, 16 KMT2Ar MPAL cases, two MPAL cases marked by BCR-ABL1 fusions, and eight individuals with unspecified MPAL.

From the exome, genome, transcriptome, and/or SNP profiles generated, the team identified 158 genes containing recurrent alterations in the leukemia cases, including genes that are frequently mutated in AML, ALL, or both. Along with alterations shared across MPAL subtypes, they described the alterations specific to the T/myeloid and B/myeloid MPAL subtypes, along with a diminished overall somatic mutation burden in the KMT2Ar MPAL cases.

Through a series of gene set enrichment analyses, mouse cell experiments, and chromatin immunoprecipitation sequencing analyses, the team began teasing apart the consequences of the ZNF384 rearrangement found in almost half of the B/myeloid MPAL cases.

The researchers used tumor sub-population sequencing on 50 MPAL cases to take a closer look at the nature of the intra-tumor heterogeneity described in MPAL — an analysis supported by methylation profiling on more than two dozen MPAL tumors, samples from normal progenitor cells, and other leukemia types. They also used xenografts models to examine lineage plasticity in sorted sub-populations of MPAL tumor cells. 

From these and other experiments, the authors concluded that "early genomic lesions prime progenitor [cells] for lineage aberrancy, which may remain stable or change over time, and that phenotype is influenced by therapeutic pressure and/or genomic evolution."

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