Research led by scientists at Cincinnati Children's Hospital Medical Center has revealed new clues into what causes different types of a particularly aggressive group of blood cancers known as mixed lineage leukemias (MLL) and how the disease might be treated, according to a study in the June 9 issue of Cancer Cell.
"We document early biological processes where human leukemia stem cells can be altered to form a particular type, or lineage, of leukemia by the factors they are exposed to in the microenvironment of blood-forming tissues," said James Mulloy, Ph.D., a researcher in the division of Experimental Hematology/Cancer Biology at Cincinnati Children's and the study's corresponding author. "These new details about molecular events associated with MLL, and the new mouse model we developed for the study, will allow testing of novel therapeutic strategies for MLL patients. They will also yield information that may be directly translatable into clinical interventions."
Leukemia is the most common blood cancer and includes several diseases, according to the National Cancer Institute. The four major types are acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic lymphocytic leukemia (CLL) and chronic myelogenous leukemia (CML).
Mixed lineage leukemia (MLL) results when chromosome mutations involving the MLL gene fuse with certain partner genes. These so-called translocations result in the MLL gene being rearranged to send instructions to create either AML or ALL. This process can start before birth, and while MLL translocations are associated with 7 percent of AML cases and 10 percent of ALL cases, they are found in a majority of infants with acute leukemia. In some instances the clinical disease is diagnosed within a few months of birth.
Dr. Mulloy and his colleagues discovered that disrupting a protein known to regulate cell growth (Rac1) has potential for curbing MLL. The discovery came about as they focused on the most common fusion partner in MLL, a gene called AF9. Previous research showed patients with MLL-AF9 fusions almost exclusively get AML, have an intermediate to poor prognosis, and that leukemia expressing MLL-AF9 is considered a more aggressive disease resistant to chemotherapy.
Although MLL-AF9 fusion is most commonly associated with AML in people, it is occasionally found in ALL as well. Dr. Mulloy's team programmed human umbilical cord blood cells to express MLL-AF9, resulting in diverse leukemia stem cells capable of transforming into either AML or ALL. The researchers influenced the transformation by altering the growth factor proteins that stimulate the differentiation and growth of blood cells, demonstrating how environmental conditions play a critical role in promoting leukemia progression and deciding disease type.
The researchers then built on this finding by adjusting the cell culture microenvironment to transform lymphoid cells into myeloid cells, as well as myeloid cells into lymphoid, highlighting the adaptability of the leukemia stem cell in mixed lineage leukemia.
"Our findings underscored that while some leukemia stem cells in MLL are diverse and able to transform into different lineages, others remain committed to a single disease type," Dr. Mulloy explained. "This information, and our ability to successfully develop human-based MLL models in mice, will be very useful in finding further insights into the early molecular events behind poor prognosis in mixed lineage leukemia."
Researchers also experimented with inducing AML or ALL in mice by using the MLL-AF9-expressing human cord blood cells. Although mouse models have been successful for studying leukemia stem cells in MLL-associated AML, their usefulness is considered limited for modeling the lymphocytic and mixed myeloid/lymphoid forms of the disease. The research team overcame this limitation by transplanting human MLL-AF9-expressing cells into two strains of mice. Both strains were bred for severe immunodeficiency (NS), which allowed human cells to be grafted into the mice. One of the strains also contained three human cytokine proteins that control blood cell formation and promote myeloid cell development (NS-SGM3).
NS-SGM3 mice receiving the MLL-AF9-programmed cells all developed AML (acute myeloid leukemia) in five to seven weeks, even when most of the MLL-AF9-expressing cells were lymphoid. The three cytokines in the mice were able to redirect the leukemia stem cells from lymphoid to myeloid. However, in the NS strain of mice, the same cells led to the development of a mix of ALL, AML and acute bi-phenotypic leukemia (ABL). In ABL, at least 20 percent of the cells have indications of both myeloid and lymphoid disease. These findings further demonstrated the importance of microenvironment in determining the lineage outcome of disease, the researchers said.
Relatively little is known about the important molecular events that are downstream of the MLL fusion gene. Previous research indicates that Rac1 – a protein that helps regulate cell growth – has increased activity in mice with AML expressing MLL-AF9. To test the importance of Rac1's downstream regulatory pathway in human AML expressing MLL-AF9, the research team experimented with a small molecule that inhibits Rac1's activity. They also tested genetic manipulation of Rac. Both interventions prevented MLL-AF9 cell growth and induced programmed cell death (apoptosis), suggesting Rac as a possible therapeutic target in AML involving rearrangement of the MLL gene, according to Dr. Mulloy and his fellow researchers.
"The exquisite sensitivity of the leukemia cells to Rac inhibition indicates that the MLL-AF9-expressing cells have become addicted to this signal, and this pathway is therefore a very good target for future drug development" said Junping Wei, M.D., Ph.D., a researcher at Cincinnati Children's and lead author of the study.
Nick Miller | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy