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  • Keynote Address
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Cooperativity between mutations in tyrosine kinases and in hematopoietic transcription factors in AML

Leukemia volume 16, pages 740–744 (2002)Cite this article

Chronic myeloid leukemia (CML) syndromes are characterized by a proliferative and/or survival advantage of myeloid lineage cells, with normal myeloid maturation and differentiation. At least six distinct chromosomal translocations have been associated with this phenotype in humans, of which the most common is the t(9;22) giving rise to BCR/ABL fusion protein. Each of these translocations associated with CML syndromes have been cloned, and invariably result in the expression of a fusion protein that has a carboxy terminal tyrosine kinase domain and an oligomerization motif on the respective amino terminus that serves to oligomerize and constitutively activate the tyrosine kinase. The transforming properties of these kinases have been demonstrated in a broad spectrum of systems, including cultured hematopoietic cell lines and murine models. For example, we have employed a bone marrow transplantation model to study the transforming properties of these fusion proteins in primary hematopoietic cells. The fusion clone is introduced into a murine ecotropic retrovirus with flanking long terminal repeat (LTR) sequences that allow for stable integration and expression of the fusion protein in bone marrow cells. The retroviral constructs are transduced into bone marrow cells from donor mice primed with 5-fluorouracil (5-FU) to bring progenitor cells into cycle and render them susceptible to retroviral transduction. Transduced bone marrow is then reinfused into lethally irradiated syngeneic recipients. When this experiment is performed with any of the fusion proteins associated with chronic myeloid leukemia syndromes in humans, including the BCR/ABL, TEL/ABL, TEL/PDGFβR or TEL/JAK2 fusions, respectively, transplanted mice die of leukemia within 50 days. Importantly, this activity is absolutely dependent on tyrosine kinase activity in that point mutations that inactivate the respective tyrosine kinase abrogate the leukemic phenotype.1,2,3,4,5,6,7,8,9,10,11,12,13

Clinically, the mice manifest a disease characterized by leukocytosis with normal maturation of myeloid lineage cells into terminally differentiated neutrophils. As in humans with chronic myeloproliferative disorders, these animals also have myeloid hyperplasia in the bone marrow, and extramedullary hematopoiesis involving myeloid lineage cells in the spleen and to a lesser extent in the liver. Thus, these tyrosine kinase fusion proteins recapitulate the human disease phenotype. In summary, CML syndromes in humans are invariably associated with constitutively activated tyrosine kinases. The tyrosine kinase fusions are sufficient to cause a CML-like disease in a murine bone marrow transplant model and, importantly, CML disease induction in this context is absolutely dependent on tyrosine kinase activity.

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    K Deguchi & DG Gilliland

  2. Harvard Medical School, Boston, MA, USA

    K Deguchi & DG Gilliland

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This paper is part of a series of keynote addresses to be published in Leukemia. They were presented at the Acute Leukemia Forum, San Francisco, 20 April 2001. Supported by an unrestricted educational grant from Immunex.

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Deguchi, K., Gilliland, D. Cooperativity between mutations in tyrosine kinases and in hematopoietic transcription factors in AML. Leukemia 16, 740–744 (2002). https://doi.org/10.1038/sj.leu.2402500

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