Northwestern scientists, in collaboration with scientists from other prominent schools, have identified the driving cause of mixed-lineage leukemia (MLL), a rare form of leukemia that affects mostly pediatric patients. The scientists have potentially found a form of therapy to treat it and other similar cancers.
On January 5, several scientists, including those from Northwestern, published an article in the science journal Cell titled, “Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia.” The scientists found that stabilizing the wild-type MLL protein can inhibit the MLL leukemia cell proliferation. In addition, scientists also found that the antibody UBE20 can be used to stabilize the wild-type MLL protein and therefore potentially manage the growth of the MLL leukemia cell.
Leukemia is a type of cancer that occurs in the blood-forming tissues. These cancerous cells in the blood can cause anemia, bleeding, infection and other symptoms. For children, leukemia is rare, and for most types the prognosis is generally good. For children with acute lymphoblastic leukemia (ALL), the most common type of cancer in children, current treatments are generally effective. Acute myeloid leukemia (AML) is rarer but also can be treated pretty well. In contrast, there are currently no approved therapies for MLL.
MLL was first noted more than 30 years ago when physicians found that a certain percentage of ALL and AML patients fared far worse than other patients. With better understanding and technology, scientists found that these leukemias expressed markers of both ALL and AML. Accordingly, this type of leukemia has been coined as mixed-lineage, a type of leukemia that primarily occurs in pediatric patients.
According to the article titled, “The molecular biology of mixed lineage leukemia,” MLL can be identified by the presence of MLL fusion proteins that are the result of chromosome 11 fusing with another chromosome. The resulting MLL fusion proteins cause increased proliferation and defects in differentiation, which basically means that dysfunctional cells end up replacing healthy red and white blood cells, which weakens the body.
The scientists of the MLL study focused on the wild-type MLL protein. Wild-type refers to the most common phenotype in nature, such as brown eyes, the wild-type phenotype for eye color in humans. There had been a lack of research on this topic – until this study. Scientists have known that the wild-type MLL protein does not drive the cancer, and that patients with MLL had low levels of the wild-type MLL protein. The scientists of the study hypothesized that higher levels of the wild-type MLL protein could potentially displace the mutant MLL and therefore evade the leukemia.
Using test mice, the scientists found that their hypothesis was correct – by stabilizing wild-type MLL protein, MLL chimeras were displaced and avoided the growth that would’ve lead to the leukemia.
While this study was done on mice, scientists believe they can use this method in treating aggressive MLL leukemia in humans. Furthermore, the scientists believe they can use this method to treat other forms of cancer caused by gene translocations.
This discovery has been a major step towards solving MLL leukemia, which has the poorest prognosis of any acute leukemia. MLL ends up occurring in 15 percent of pediatric acute leukemia cases, but has there still have not been any approved therapies for the condition. This breakthrough, finding the driving cause of mixed-lineage leukemia, is a major step towards finding a permanent therapy.
The Northwestern scientists involved in this study include Kaiwei Liang, Andrew G. Volk, Stacy A. Marshall, Ashley R. Woodfin, Elizabeth T. Bartom, Edwin R. Smith, John D. Crispino and Ali Shilatifard.