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Sequencing Study Suggests Potential New Treatments for ALL Subset with Poor Response


By Molika Ashford

A study by St. Jude Research Hospital and Washington University in St. Louis has discovered patterns of mutations in an aggressive subtype of acute lymphoblastic leukemia that suggest the cancer may respond to therapies used to treat a different hematologic cancer.

The group sequenced the whole genomes of patients with early T-cell precursor ALL, a subtype of ALL associated with a high risk of treatment failure. Reviewing the full list of mutations and their linked pathways, the group found that the overall spectrum of gene changes suggest the subtype may be less like other T-cell ALLs and more like acute myeloid leukemia. Because of this, drugs used more successfully in treating AML — either targeted or broadly chemotherapeutic — could improve the poor outcome of ETP ALL, the group reported.

The study was part of the Pediatric Cancer Genome Project, an effort spearheaded by St. Jude and Wash U to sequence the genomes of at least 600 childhood cancer patients. The researchers published their results earlier this month in Nature.

According to Charles Mullighan, a St. Jude pathologist and one of the study's corresponding authors, the findings are not conclusive enough to suggest that ETP ALL patients should begin any of these treatments right away, or which drugs might be the most beneficial.

However, the disease's aggressive course has spurred a lot of interest in the results, according to Mullighan. Patients with ETP ALL respond so poorly to current drug regimens, the group decided to include ETP ALL in the PCGP due to the "urgent" need to identify new treatments for these patients.

ETP ALL is a relatively rare cancer, Mullighan said, making up only about fifteen percent of T-cell ALLs, which are themselves only 15 percent of all ALL cases.

"It's not that we get a hundred of these every year at St. Jude. We only get a handful. So, how we change therapy has to be discussed very carefully because it may be we only get to choose one of these agents for the next year or so to see which one is the most rational," he explained.

"So we're not immediately testing one of these drugs but I think therapy will change to include a novel agent in a trial-based setting in the not-too-distant future," he said.

After Mullighan and his colleagues had little success using approaches such as SNP arrays and candidate gene sequencing to investigate the genetic lesions underlying the cancer subtype, they agreed that this was "an ideal group to sequence, as a very poor risk subtype, with little known about underlying genetics and an urgent need for new treatments."

In the study the group sequenced the whole genomes of 12 subjects with matched tumor and normal DNA and then assessed the frequency of the identified mutations in a cohort of 94 additional T-cell ALLs — 52 patients with ETP ALL and 42 with non-ETP childhood T-cell ALL.

Overall, the researchers saw that there were three pathways that were the most frequently mutated in the ETP ALL subjects. One involved loss-of-function mutations controlling normal blood cell development. Another involved activation of proliferative mutations in cytokine receptors and RAS signaling. The third traced mutations that regulate chromatin modeling and modification, he said.

While most of the specific genes mutated in these pathways were different in ETP ALL than those in AML, the study suggested that mutations in the same pathways may drive the two diseases.

In medical practice, ETP ALL patients are currently clumped together with other ALLs, and end up receiving rotating chemotherapy cocktails, up to eight or nine agents over several years. Physicians assess patient response in several ways, looking at the proportion of leukemic cells in the bone marrow, as well as molecular and flow-cytometric markers.

About a month after treatment, most ALL patients may not have visible leukemic cells, Mullighan noted, but may still have leukemia present. ALL patients can relapse even though they may appear to have very good early response to treatment.

While ETP ALL patients can similarly relapse despite initial response to treatment, more frequently doctors see in this subset of patients that even initial therapy fails. "We don't even get into what we call a morphological remission, meaning we can't see the leukemic cells in bone marrow," said Mullighan.

St. Jude researchers identified the ETP ALL subtype several years ago, noting that a group of T-cell ALL patients had an unusual pattern of immunophenotype markers. While they lacked some expression markers seen in more mature T-cell ALL, they had other markers seen in AML or in hematopoietic stem cells.

Because of the resemblance to early T-cell precursors, the name was coined early T-cell ALL.

In this study, the researchers found some gene mutations in ETP ALL that are also common in AML. For example, RUNX1, which is often mutated in AML, was similarly "mutated and deleted and translocated in some of our ETP cases," Mullighan said.

But there were several hits that did not match with AML mutations. For instance, the team found loss-of-function mutations and deletions of GATA2 that have never been seen in AML to the group's knowledge.

"On one level it may be too simplistic to say the pathway is the same so we should treat it the same," Mullighan said. "But there were other reasons to think that as well."

In addition to noting that ETP ALL's mutated pathways reflected those of AML, the researchers also knew that some EPT ALL cells express markers seen in AML cells, he noted.

The group also compared gene expression profiles in their study. "What we call an ETP ALL was based on a fairly limited set of data from a few years ago, so we thought, what if we now take the most up-to-date gene expression profiles from these leukemias and compare to as many leukemic and non-leukemic signatures as we can find," said Mullighan.

This showed that at the gene-expression level, ETP ALL didn't look like T-cell leukemia but more like primitive stem-cell leukemia. There was also similarity between the gene expression signature of ETP ALL cases and high-risk AML signatures, Mullighan said.

"So there were multiple levels of evidence … that all suggested that there were more features of AML than we would otherwise expect to see in T-cell ALL."

AML therapies range from targeted to very general, Mullighan said. One drug, cytarabine, is not usually used in frontline ALL treatment, but serves as the backbone of AML treatment. "There's a lot of discussion now about whether it should be explored out front in ALL," Mullighan said.

Another option might be more targeted therapies. Many cases the St Jude team sequenced had mutations implicated in JAK signaling. Not all patients had obvious mutations, Mullighan said, but the team's gene expression profiling showed that the pathway was activated in "virtually every patient."

"We have good, extensively studied, off-the-shelf drugs that target the JAKs. So they might be pursued as well," he added.

The research team is also using biological modeling and has created a panel of xenographic mice to look at other possible treatments. This preclinical work is ongoing.

Because ETP ALL is distinguished not by genetics but through flow cytometry, Mullighan also said that it may be that the ETP subset actually covers a slightly different, and potentially broader footprint of leukemias. This suggests that identifying a clearer boundary for what is and isn't ETP ALL could help solidify which treatments to try.

"There's now a lot of discussion in the field, with people saying if we use these parameters we get a slightly different group of cases, [and] I think this comes down to the fact that there are probably different similar cases that are diagnosed as different kinds of leukemia that we haven’t studied yet," he noted.

For this reason the researchers are also interested in looking more carefully at other types of leukemia to see how common this subtype currently called ETP ALL really is overall.

"My strong suspicion is that this is probably only a fraction," Mullighan said. "It might be a majority, but we think there are probably other cases being diagnosed as other types, such as AML, and because they also do badly it's important to tackle those as well."

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