Researcher – Dr. Stephan W. Morris
Facility – St. Jude Children’s Research Hospital
Location – Memphis, TN
Amount - $50,000

The Problem – Two of the most common blood cancers are acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Each of these cancers can be divided into subtypes characterized by the unique genetic characteristics of the leukemias. One highly prevalent subtype of acute leukemia arises due to the abnormal fusion of the gene encoding the mixed-lineage leukemia (MLL) protein to a large variety of partner genes.

MLL fusion leukemias are the most common form of leukemia in infants, but occur in all age groups. The expression of an MLL fusion protein is associated with a very poor prognosis regardless of the age of the patient (for example, the 10-year survival for MLL fusion-positive ALL for all ages is ~30% compared to 60-95% for all other ALL subtypes).

The poor response of MLL fusion-expressing leukemias to conventional treatments emphasizes the need for novel, targeted therapies for these hematopoietic malignancies. Recent data suggest that specific protein-protein interactions involving MLL fusion proteins are critical for the development and progression of leukemia (leukemogenesis), and interruption of these interactions inhibits proliferation and induces cell death of MLL fusion-positive leukemias.

The Morris research group identified a peptide made from the region of MLL that interacts with the menin protein. This peptide blocks the MLL-menin interaction and induces cell death in leukemia cells expressing MLL fusion proteins while not harming normal cells.

In its WES Foundation studies, the Morris laboratory proposed to determine the structures of the interaction sites of MLL and menin, and to ultimately work toward the design and synthesis of small molecules that inhibit the interaction of menin and MLL that would be more drug-like than the blocking peptide. Such a small-molecule inhibitor could potentially be developed as a targeted therapy for the MLL fusion leukemias.

The Result – Additional studies using the originally identified blocking peptide allowed the Morris lab to further refine their understanding of the nature of the MLL-menin protein:protein interaction. For example, the group identified the specific portions within the peptide (i.e., the exact amino acids) that are most critical for mediating the physical association between MLL and menin.

Unfortunately, progress in determining the three-dimensional structure of menin at the location of its interaction with MLL was somewhat hampered by technical problems in isolating and purifying the human menin protein. Similar technical problems were also encountered by another group of academic investigators who were working independent of the Morris group. As an intermediate step toward ultimately solving the human menin protein structure, this group instead opted to purify and determine the crystal structure of the menin protein from the starlet sea anemone (Nematostellavectensis), which has considerable relatedness to human menin.

Given their common interest in the MLL-menin interaction and its importance as a leukemia target, Dr. Morris has recently starting working with this other group of academic investigators in order to collaboratively further their mutual scientific discovery efforts.

What we learned - Critical information concerning the most essential amino acids that mediate the physical interaction between the MLL and menin proteins was obtained. These results are critical in that they will help inform the scientifically rational design of small-molecule drugs that efficiently block the MLL-menin interaction. Such drugs will be candidates for clinical development as new agents to treat MLL fusion leukemias.

Where do we go from here? - The basic research insights described above together with the establishment of productive working relationships between Dr. Morris and other scientific investigators working in the MLL leukemia field - both of which were made possible by the funding received from the WES Foundation - have recently enabled substantive efforts directed toward the actual commercial development of both a diagnostic test and therapeutic agent to target MLL-driven leukemias.

Specifically, Dr. Morris decided to leave academic medicine in early 2012 to found clinical diagnostic (Insight Genetics, Inc.) and therapeutic (IG Therapeutics, Inc.) companies (www.insightgenetics.com). Insight Genetics is currently developing a companion diagnostic assay to identify patients whose leukemias are caused by MLL genetic abnormalities (and who would therefore be predicted to respond to MLL-menin inhibitors), and IG Therapeutics is in late-stage discussions to in-license and develop in clinical trials a small-molecule MLL-menin inhibitor discovered by a group of scientists from a large US university.

Dr. Morris has promised to keep the WES Foundation and its contributors up to date as he and his colleagues pursue the development of this MLL leukemia targeted therapy agent and the associated diagnostic test.

Researcher – Dr. Gregor Reid
Facility – Children’s Hospital of Philadelphia
Location – Philadelphia, PA
Amount - $50,000

The Problem- For children with leukemia who are not cured by current therapy the outcome is poor. More of the same therapy is not very effective against leukemia when it returns and new treatments are needed to help these children. As leukemia in children is the result of abnormal cells that grow for a long time before disease starts, we wanted to see if getting rid of these cells would be an effective way of stopping the disease.

The Result - Using mice that get a similar leukemia to children, we showed that eliminating the abnormal cells that give rise to leukemia does indeed prevent the disease from starting.

What We Learned - By showing that it is possible to stop leukemia before it starts, our results suggest that finding ways to eliminate the abnormal cells may prevent the disease from returning in children after therapy.

Where do we go from here? – Based on these results, we are working hard to find a way to eliminate the abnormal cells in children. Our early work suggests that the child’s own immune system could be stimulated to attack these cells and so we are now investigating the most effective ways of kick-starting these immune responses.