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Double Knockout of the ALL-1 Gene Blocks Hematopoietic Differentiation in Vitro¹

The Jefferson Cancer Institute and the Jefferson Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107 [V. F., P. M., T. Y., T. N., B. C., C. M. C.]; The Institute of Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030 [A. B.]; and Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel [E. C.]

The ALL-1 gene is involved in translocations with many partner genes in different types of acute leukemias, but it is not clear whether it acts as an oncogene or whether the fusion proteins resulting from the translocations have dominant negative effects. To distinguish between these two possibilities, we analyzed the ability of wild-type AB2.1 embryonal stem (ES) cells and of single or double ALL-1 gene knockout cells derived from them to differentiate along hematopoietic lineages after withdrawal of leukemia inhibitory factor, using in vitro colony formation assays. ALL-1 double knockout ES cells formed a significantly greater number of colonies with faster kinetics than wild-type and ALL-1 single knockout ES cells. Parental ES cells formed lineage-restricted colonies, whereas single and double knockout ES cells developed, at high frequency, immature and/or "biphenotypic" colonies, mimicking the aberrant hematopoiesis typical of leukemic patients. These data are consistent with the possibility that loss of function of the ALL-1 gene is important in leukemogenesis.

¹ This study was supported by the Falk Medical Research Trust, by Outstanding Investigator Grant CA 39860 from the National Cancer Institute, by National Cancer Institute Grant PO1 CA 50507, and by American Cancer Society Grants DHP-81 and DHP-3D. P. M. was supported in part by a fellowship of the Associazione Italiana per la Ricerca sul Cancro.

² The first two authors contributed equally to this work.

³ To whom requests for reprints should be addressed, at Jefferson Cancer Institute, Thomas Jefferson University, BLSB, Room 1050, 233 South 10th Street, Philadelphia, PA 19107-5799.

Received 1/ 5/96. Accepted 1/31/96.

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