Model reveals that protein induces preleukemic state, hampering blood cell differentiation and creating abnormal blood cell progenitors 

January 17, 2006 

WORCESTER, Mass. - Scientists at the University of Massachusetts Medical School have developed a novel mouse model for leukemia that reveals critical information about the mechanisms involved in leukemia progression and provides a model system for evaluation of new drugs for the treatment of leukemia. The research, led by Lucio H. Castilla, PhD, assistant professor of molecular medicine, and published in the January issue of Cancer Cell, utilizes a technique that allows for the previously unattainable induction and study of a key oncoprotein in adult mice.

The common form of leukemia affecting adults, acute myeloid leukemia (also called AML) can arise from genetic alterations in bone marrow cells that give rise to blood cells. In this study, Dr. Castilla and colleagues in the Medical School's Program in Gene Function and Expression have focused on the oncogenic properties of CBFbeta-SMMHC - a fusion protein-created by joining portions of two different genes - known to be present in about 12% of human AML cases.

To expand on previous research which demonstrated that CBFbeta-SMMHC had a dominant effect over expression of genes that are very important in blood cell development, the Castilla lab had to develop a means to study the expression of the protein in adult mice because the expression of the fusion protein was previously associated with embryonic lethality. In order to determine how blood development is altered due to the expression of CBFbeta-SMMHC, the researchers created a conditional knock-in mouse model where the expression of the fusion gene is not induced until the mouse reached adulthood, when scientists can selectively trigger the expression of the fusion protein.

Castilla and colleagues found that CBFbeta-SMMHC induction was associated with a reduction of immature blood cells in the bone marrow as well as with the appearance of abnormal progenitor cells that are leukemic precursors. Mice expressing CBFbeta-SMMHC developed AML with a median latency of approximately 5 months with the time of disease onset varying with the number of abnormal cells in the bone marrow. Interestingly, additional studies showed that the blood stem cell precursors that expressed CBFbeta-SMMHC were maintained at normal levels for long periods of time but that their ability to differentiate into multiple types of blood cells was severely compromised.

The results of study open the possibility that fusion proteins, like CBFbeta-SMMHC, that interfere with differentiation of blood cells may maintain normal numbers of blood stem cell precursors for a long time, but that these precursors may not be able to repopulate the blood adequately. In addition, such fusion proteins may induce formation of abnormal precursor cells that are targets for the development of AML.

"This model will be key for the study of early target genes in blood cell progenitors and the evaluation of candidate drugs for improved treatment of AML," said Castilla. "We also know that the while expression of this fusion protein is not sufficient to the development of leukemia, it is necessary for the development. Our goal in future research is to continue to identify those cooperating genes that enhance the progression of this devastating disease."

The University of Massachusetts Medical School, one of the fastest growing academic health centers in the country, has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research.  The Medical School attracts more than $174 million in research funding annually, 80 percent of which comes from federal funding sources. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. For more information visit


Kelly Bishop, 508-856-2000