Autocrine and paracrine effects of an ES-cell derived, BCR/ABL-transformed hematopoietic cell line that induces leukemia in mice

David G. Peters, Kevin M. Klucher, Rita C.R. Perlingeiro, Scott K. Dessain, Eugene Y. Koh, George Q. Daley

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

During differentiation in vitro, Embryonic Stem (ES) cells generate both primitive erythroid and definitive myeloid lineages in a process that mimics hematopoiesis in the mammalian yolk sac. To investigate leukemic transformation of these embryonic hematopoietic progenitors, we infected differentiating cultures of ES cells with the Chronic Myeloid Leukemia-specific BCR/ABL oncoprotein. Following a period of liquid culture, we isolated two transformed subclones, EB57 and EB67, that retained characteristics of embryonic hematopoietic progenitors and induced a fatal leukemia in mice characterized by massive splenomegaly and granulocytosis. Histopathology of the spleen revealed an abundance of undifferentiated blast-like cells. Investigation of the clonal origins of the granulocytes in the peripheral blood demonstrated that the injected donor cells contributed modestly to the granulocyte population while the majority were host-derived. EB57 secretes IL-3 and unidentified cytokines that can stimulate autocrine and paracrine cell proliferation, presumably accounting for the reactive granulocytosis in diseased mice. These BCR/ABL transformed hematopoietic derivatives of ES cells recapitulate the relationship of BCR/ABL expression to IL-3 production that has been described for primitive hematopoietic progenitors from human CML patients, and illustrates the potential for autocrine and paracrine effects of BCR/ABL-infected cells in murine models.

Original languageEnglish (US)
Pages (from-to)2636-2646
Number of pages11
JournalOncogene
Volume20
Issue number21
DOIs
StatePublished - May 10 2001
Externally publishedYes

Bibliographical note

Funding Information:
Supported by the National Science Foundation-MIT Biotechnology Process Engineering Center, NCI grant CA76418-01 and CA86991-01, and the Burroughs Wellcome Fund. GQ Daley is a scholar of the Edward C. Mallinckrodt Jr Foundation and the Birnbaum Scholar of the Leukemia and Lymphoma Society of America. SK Dessain is supported by the Lauri Strauss Leukemia Foundation and NIH K08 HL 04463.

Keywords

  • BCR/ABL
  • Chronic myeloid leukemia
  • Embryonic stem cell
  • Interleukin-3

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