Mouse model reveals that oncoprotein induces abnormal preleukemic blood cell progenitors

Scientists 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 treatment of leukemia. The research, published in the January issue of Cancer Cell, utilizes a technique that allows induction and study of a key oncoprotein in adult mice. Previously, it was difficult to investigate this oncoprotein in the mouse, as the expression of this gene is associated with embryonic lethality, or death of the developing mouse in utero.

Acute myeloid leukemia (AML) can arise from genetic alterations in the bone marrow cells that give rise to blood cells. One fusion oncoprotein that is present in about 12% of human AML cases and is known to interfere with the process of normal blood cell development is called CBFB-SMMHC. Thus far, this protein has been very difficult to study in mouse models, as its expression causes embryonic lethality. Dr. Lucio H. Castilla from the Program in Gene Function and Expression at the University of Massachusetts Medical School and colleagues created a conditional mouse model to analyze the preleukemic effects of CBFB-SMMHC on blood cell production and AML development in adult mice. The mouse model enabled the scientists to selectively turn on expression of CBFB-SMMHC in adult mice, thereby avoiding embryonic lethality of expression of this gene, and then study the effects.

The researchers found that CBFB-SMMHC induction was associated with a reduction of immature blood cells in the bone marrow and with the appearance of abnormal progenitor cells that are leukemic precursors. Mice expressing CBFB-SMMHC developed AML with a median latency of approximately five 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 CBFB-SMMHC were maintained at normal levels for long periods of time, but their ability to differentiate into multiple types of blood cells was severely compromised.

The researchers conclude that some leukemia fusion proteins that interfere with differentiation of blood cells may maintain normal numbers of blood stem cell precursors, 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 development of AML, essentially existing as cancer causing "time bombs" in the bone marrow. According to Dr. Castilla, "this model will be key for the study of early target genes in blood cell progenitors and the in vivo validation of cooperating oncogenes, as well as for the evaluation of candidate drugs for improved treatment of AML."

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The researchers include Ya-Huei Kuo, Sean F. Landrette, Susan A. Heilman, Paola N. Perrat and Lucio H. Castilla of the University of Massachusetts Medical School in Worcester, MA; Lisa Garrett and Pu P. Liu of the National Institutes of Health in Bethesda, MD; Michelle M. Le Beau of the University of Chicago in Chicago, IL; Scott C. Kogan of the University of California, San Francisco in San Francisco, CA. This work was supported by National Institutes of Health grants R01-CA096983 (to L.H.C.) and CA84221 (to S.C.K. and M.M.L.), and by a Specialized Center of Research (SPOR) grant (7019-04 to M.M.L.) from the Leukemia & Lymphoma Society; Y-H. K. was partly supported by the Our Danny Cancer Fund grant and by Ruth L. Kirschstein NationalResearch Service Award (F32CA101571).

Kuo et al.: "CbfB-SMMHC induces distinct abnormal myeloid progenitors able to develop acute myeloid leukemia." Publishing in Cancer Cell, Vol. 9, January 2006, pages 5768. DOI 10.1016/j.ccr.2005.12.014 www.cancercell.org


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