Priority Research Papers:

Loss of Egr1, a human del5q gene, accelerates BCR-ABL driven chronic myelogenous leukemia

Silvia Maifrede, Andrew Magimaidas, Xiaojin Sha, Kaushiki Mukherjee, Dan A. Liebermann and Barbara Hoffman _

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Oncotarget. 2017; 8:69281-69294. https://doi.org/10.18632/oncotarget.20612

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Silvia Maifrede1,3,*, Andrew Magimaidas1,2,*, Xiaojin Sha1, Kaushiki Mukherjee1, Dan A. Liebermann1,4 and Barbara Hoffman1,4

1 Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA

2 Current address: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania

3 Department of Microbiology and Immunology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA

4 Department of Medical Genetics and Molecular Biochemistry, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA

* Co-first author

Correspondence to:

Barbara Hoffman, email:

Keywords: Egr1, chronic myelogenous leukemia, stress response protein, tumor suppressor, Leukemic stem cells

Received: May 11, 2017 Accepted: August 04, 2017 Published: September 01, 2017


There is substantial evidence that early growth response-1 (Egr1) gene, a zinc-finger transcription factor, behaves as a tumor suppressor in leukemia. This includes reports from this laboratory that constitutive Egr1 overrides leukemia conferred by deregulated c-Myc or E2F-1 in the M1 myeloid leukemic cell line by promoting differentiation. To investigate the effect of Egr1 on the initiation and progression of Chronic Myelogenous Leukemia (CML), lethally irradiated syngeneic wild type mice were reconstituted with bone marrow (BM) from either wild type or Egr1 null mice transduced with a 210-kD BCR-ABL-expressing MSCV-retrovirus (bone marrow transplantation {BMT}). Loss of Egr1 was observed to accelerate the development of BCR-ABL driven leukemia in recipient mice, resulting in the development of a more aggressive disease, a significantly shortened median survival time, and increased BCR-ABL expressing leukemic stem/progenitor cells (GFP+Lin-cKit+Sca+). Egr1 deficient progenitors expressing BCR-ABL exhibited decreased apoptosis, and increased cell viability and proliferation relative to WT counterparts. Secondary BMT of BCR-ABL BM revealed that loss of Egr1 resulted in enrichment of LSCs, consistent with shorter survival time and more aggressive disease of these mice compared to WT counterparts. Furthermore, serial re-plating colony assays indicated that loss of Egr1 increased self-renewal ability of BCR-ABL expressing BM. These novel findings on the tumor suppressor role of Egr1 in CML provide the impetus to study the effect of altering Egr1 expression in AML, where the overall five year survival rate remains low. The effect of loss of Egr1 in CML could reflect its established functions in normal hematopoiesis, maintaining quiescence of HSCs and driving terminal differentiation to the monocyte/macrophage lineage. Gain of function studies should validate these conclusions and provide further rationale for increased Egr1 as a therapeutic target in AML.

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