Chronic Myeloid Leukemia with Increased Granulocyte Progenitors in Mice Lacking JunB Expression in the Myeloid Lineage

Abstract

The functions of JunB during myelopoiesis were studied in vivo. Transgenic mice specifically lacking JunB expression in the myeloid lineage (junB(-/-)Ubi-junB mice) develop a transplantable myeloproliferative disease eventually progressing to blast crisis, which resembles human chronic myeloid leukemia. Similarly, mice reconstituted with ES cell-derived junB-/- fetal liver cells also develop a myeloproliferative disease. In both cases, the absence of JunB expression results in increased numbers of granulocyte progenitors, which display enhanced GM-CSF-mediated proliferation and extended survival, associated with changes in the expression levels of the GM-CSFalpha receptor, the anti-apoptotic proteins Bcl2 and Bclx, and the cell cycle regulators p16(INK4a) and c-Jun. Importantly, ectopic expression of JunB fully reverts the immature and hyperproliferative phenotype of JunB-deficient myeloid cells. These results identify JunB as a key transcriptional regulator of myelopoiesis and a potential tumor suppressor gene.

AP‐1: Linking Hydrogen Peroxide and Oxidative Stress

“…As expected, the transgene suppressed the embryonic lethality associated with the loss of JunB, but the rescued mice were found to develop highly penetrate myeloid leukemia (50). Further analysis of these mice revealed a surprising but highly speci c extinction of the junB transgene in cells of the myeloid lineage, causing myeloid cells to remain JunB-de cient, whereas all other cell types express JunB (50). The absence of JunB in myeloid cells prevented the induction of p16 INK4a expression associated with terminal differentiation of granulocytes, resulting in the continued proliferation and eventual transformation of granulocytic progentitors (50).…”

“…As expected, the transgene suppressed the embryonic lethality associated with the loss of JunB, but the rescued mice were found to develop highly penetrate myeloid leukemia (50). Further analysis of these mice revealed a surprising but highly speci c extinction of the junB transgene in cells of the myeloid lineage, causing myeloid cells to remain JunB-de cient, whereas all other cell types express JunB (50).…”

“…Further analysis of these mice revealed a surprising but highly speci c extinction of the junB transgene in cells of the myeloid lineage, causing myeloid cells to remain JunB-de cient, whereas all other cell types express JunB (50). The absence of JunB in myeloid cells prevented the induction of p16 INK4a expression associated with terminal differentiation of granulocytes, resulting in the continued proliferation and eventual transformation of granulocytic progentitors (50). The differences in JunB and c-Jun function may be cell-type speci c, as replacement of c-jun with junB prevents the mid-gestation lethality associated with the loss of c-Jun (E. Wagner, personal communication).…”

JunB is a gatekeeper for B-lymphoid leukemia

“…Observations in these models suggest an important role of JunB in hematopoesis. In junB À/À mice intercrossed with UbijunB mice, silencing of the transgene is associated with myeloid hyperproliferation, which progresses to a chronic myeloid leukemia (CML)-like disease (Passegue et al, 2001). A similar phenotype is observed upon conditional deletion of junB in the embryo (junB D/D mice) (Passegue et al, 2004).…”

JunB and PTEN in prostate cancer: ‘loss is nothing else than change’

“…9 This is consistent with the tumorsuppressive functions of JunB in the myeloid and lymphoid lineages. 10,11 In this issue, Thomsen et al investigated the role of JunB in the PSA-Cre mediated Pten knockout mouse model, which enables the investigation of the time window from low-grade prostate intraepithelial neoplasia (PIN) to high-grade PIN lesions, which is of special human relevance. 12 Their results provide yet another in vivo hint as to the tumor-suppressive function of mitogenic signaling mediators.…”