Possible New Treatment Approaches Identified for ETP-ALL

Roxanne Nelson

January 13, 2012

January 13, 2012 — The first details of genetic alterations that underlie early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) have come from a study that sequenced multiple genomes of this leukemia subtype. The results of this sequencing suggest that ETP-ALL is more closely linked to acute myeloid leukemia (AML) than to other subtypes of ALL.

"The pathways are similar, and several of the individual genes are shared between ETP-ALL and AML," explained study author Charles Mullighan, MD, PhD, from the Department of Pathology at St. Jude Children's Research Hospital, Memphis, Tennessee. "But there are some genes that are mutated in AML that we don't see in ETP-ALL."

"Conversely, we have some quite novel targets of mutation in ETP that never mutated in AML, at least not in studies that are being performed today," he told Medscape Medical News.

The findings appear in the January 12 issue of Nature.

The mutations and gene-expression profile that were identified in this study suggest that patients with ETP-ALL will benefit from treatment that includes drugs developed to treat AML.

"We don't have a definitive answer of what the best treatment would be," Dr. Mullighan said, "but we do have a number of very important new options.

"At the moment, the treatment we use for AML and ALL are quite distinct," he continued. "We might use some of the drugs that are currently used in AML...in ETP-ALL to see if they have a better effect."

He cautioned that although they might show some efficacy, they are not magic bullets. "They are nontargeted agents that treat all dividing cells," he said. "An example is cytarabine, which is a backbone of therapy in AML; that option is being explored."

Targeted therapies are another option that is being explored. "One of the pathways that has been found to be mutated in high frequency is cytokine-receptor and RAS signaling," explained Dr. Mullighan. "Existing drugs that target these pathways may be an option."

The third option, which has not yet been explored, but which will be, is that of epigenetic regulation, he continued. "An interesting pathway that we found mutated at high frequency is histone modification, which again is not a novel concept."

"This pathway and epigenetic regulators are mutated in lymphoma and AML, and they are being actively pursued as therapeutic targets," Dr. Mullighan said. "We found several new targets and mutations. The question is whether some of the drugs that modify epigenetic regulation will be suitable in this setting."

Aggressive Subtype

ETP-ALL comprises up to 15% of all cases of T-lymphoblastic ALL (T-ALL), and is associated with a high risk for treatment failure. An estimated 30% to 40% of patients become long-term survivors, compared with about 80% of children diagnosed with other T-ALL subtypes.

This unique biologic subtype of childhood T-ALL was identified by researchers at St. Jude's several years ago. Researchers found that these patients do not respond as well as typical T-ALL patients to standard intensive chemotherapy, and that they have a much worse prognosis.

The researchers performed whole-genome sequencing for matched leukemic and normal DNA from 12 children with ETP-ALL. The sequencing was part of the 3-year Pediatric Cancer Genome Project, conducted by St. Jude Children's Research Hospital and Washington University in St. Louis, Missouri, which was launched in 2010. ETP-ALL was selected for inclusion because of its poor outcome and the lack of information on its genetic alterations.

Multiple Patterns of Mutations

In addition to whole-genome sequencing in 12 patients with ETP-ALL, the team also looked at the frequency of mutations in a separate group of 52 children with ETP-ALL and 42 with non-ETP-T-ALL, of which 82 had matched remission DNA.

The authors observed mutations that were unique to ETP-ALL and not seen in other subtypes of ALL; the pattern of mutations was reminiscent of changes associated with AML, Dr. Mullighan said.

ETP-ALL was characterized by activating mutations in genes regulating cytokine-receptor and RAS signaling pathways. These mutations include NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3, and BRAF, which were detected in 67% of ETP-ALL cases.

Mutations of genes that regulate cytokine-receptor and/or RAS signaling pathway and epigenetic modification are common features of AML, note the authors, but it is less commonly observed in T- or B-cell lineage.

Inactivating lesions that disrupt hematopoietic development were found in 58% of ETP-ALL patients; the genes involved include GATA3, ETV6, RUNX1, IKZF1, and EP300.

Epigenetic mutations were also more common in ETP-ALL patients (48%), and histone-modifying genes include EZH2, EED, SUZ12, SETD2, and EP300. New targets of recurrent mutation, including DNM2, ECT2L, and RELN, were also identified.

The authors note that even though the gene-expression profile of ETP-ALL is similar to that of the murine ETP, it also has a strong similarity to the profiles of normal and myeloid leukemic hematopoietic stem cells. "This indicates that ETP-ALL is distinct from non-ETP-T-ALL, and in fact represents a neoplasm of a less mature hematopoietic progenitor or stem cell, with arrest at a very early maturational stage that retains the capacity for myeloid differentiation," they write.

This observation raises the possibility that therapeutics currently used to treat AML, including "those incorporating high-dose cytarabine, and/or targeted therapies that inhibit cytokine-receptor and JAK signaling may be beneficial in ETP-ALL," the authors note.

The research was funded in part by the Pediatric Cancer Genome Project, the National Institutes of Health, Washington University, the National Human Genome Research Institute, the National Cancer Institute, Alex's Lemonade Stand, St. Baldrick's Foundation, and ALSAC. Coauthor Sue Heatley, from St. Jude Children’s Research Hospital, was supported by the Haematology Society of Australasia and the New Zealand New Investigator Scholarship.

Nature. 2012;481:157-163. Abstract

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