Abstract
An understanding of how each individual 5q chromosome critical deleted region (CDR) gene contributes to malignant transformation would foster the development of much needed targeted therapies for the treatment of therapy related myeloid neoplasms (t-MNs). Early Growth Response 1 (EGR1) is a key transcriptional regulator of myeloid differentiation located within the 5q chromosome CDR that has been shown to regulate HSC (hematopoietic stem cell) quiescence as well as the master regulator of apoptosis—p53. Since resistance to apoptosis is a hallmark of malignant transformation, we investigated the role of EGR1 in apoptosis of bone marrow cells; a cell population from which myeloid malignancies arise. We evaluated radiation induced apoptosis of Egr1+/+ and Egr1-/- bone marrow cells in vitro and in vivo. EGR1 is not required for radiation induced apoptosis of murine bone marrow cells. Neither p53 mRNA (messenger RNA) nor protein expression is regulated by EGR1 in these cells. Radiation induced apoptosis of bone marrow cells by double strand DNA breaks induced p53 activation. These results suggest EGR1 dependent signaling mechanisms do not contribute to aberrant apoptosis of malignant cells in myeloid malignancies.
Highlights
Myeloid malignancies are clonal diseases which arise from hematopoietic stem or progenitor cells [1]
Early Growth Response 1 (EGR1) has been shown to be important for apoptosis induction in several model systems and is one of the deleted genes located in the common deleted region (CDR) of therapy related myeloid neoplasms (t-myeloid neoplasms (MN)) with del (5q)
EGR1 in apoptosis of bone marrow cells, Egr1+/+ and Egr1-/- bone marrow mononuclear cells (BM-MNCs) enriched for primitive cells by depletion of mature lymphoid and myeloid cells were exposed to ionizing radiation (2 Gy and 6 Gy) and apoptosis was assessed by annexin-V staining 24Hrs post radiation
Summary
Myeloid malignancies are clonal diseases which arise from hematopoietic stem or progenitor cells [1]. Several genetic alterations have been identified in myeloid neoplasms (MN) but our understanding of their individual effects and how they each contribute to disease development is still limited [1]. Such understanding will facilitate separation of driver mutations from the plethora of background mutations, enhancing our ability to develop targeted treatments as was demonstrated by the identification and characterization of the break point cluster region-abelson (Bcr-Abl). Though the 5q chromosomal deletions that occur in t-MNs are typically very large, uncharacteristically smaller deletions occur in a few patients [7, 8] These uniquely smaller deletions facilitated delineation of the critical or common deleted region (CDR) by gene mapping [4, 7, 8]
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