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Src family kinase gene targets during myeloid differentiation: identification of the EGR-1 gene as a direct target

Leukemia volume 23, pages 1933–1935 (2009)Cite this article

The prospect of applying differentiation therapies to the treatment of acute myeloid leukemias (AMLs) is highlighted by the use of all-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL). Treatment with ATRA in combination with chemotherapy or arsenic trioxide results in cure in the majority of patients with either newly diagnosed or recurrent APL.1 The effectiveness of ATRA is because of the induction of differentiation in the APL leukemic blasts and their conversion to a nonproliferative state. However, ATRA is largely ineffective at inducing differentiation in non-APL subtypes of AML, and differentiation therapies for these other subtypes have not been developed. Therefore, it is important to identify the cellular signaling pathways that are aberrantly activated and act to inhibit myeloid differentiation in AML cells.

Previous studies have shown that Src family kinases (SFKs) are overexpressed and/or hyperactivated in AML cell lines and primary cells. SFKs are non-receptor tyrosine kinases that have been implicated in a variety of physiological process, including proliferation, survival, differentiation and migration. In all nine different SFKs have been identified, although the expression in myeloid lineage cells appears more restricted to the SFKs Lyn, Fgr, Hck and c-Src.2 To determine the role of SFKs in regulating myeloid differentiation, we previously employed the pan-SFK inhibitors PP1 and PP2. Pharmacological inhibition of SFKs using PP1 or PP2 was found to markedly enhance ATRA-induced myeloid differentiation of AML cell lines, as well as primary cells from a patient with non-APL AML.3 These findings showed that SFKs act as negative regulators of ATRA-induced myeloid differentiation.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    J E Jones, L Wang, P L Kropf, R Duan & D E Johnson

  2. Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA, USA

    D E Johnson

Authors
  1. J E Jones
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  2. L Wang
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  3. P L Kropf
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  4. R Duan
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  5. D E Johnson
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Correspondence to D E Johnson.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Jones, J., Wang, L., Kropf, P. et al. Src family kinase gene targets during myeloid differentiation: identification of the EGR-1 gene as a direct target. Leukemia 23, 1933–1935 (2009). https://doi.org/10.1038/leu.2009.118

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