Mcl-1 in Transgenic Mice Promotes Survival in a Spectrum of Hematopoietic Cell Types and Immortalization in the Myeloid Lineage

Abstract

Mcl-1 is a member of the Bcl-2 family that is expressed in early monocyte differentiation and that can promote viability on transfection into immature myeloid cells. However, the effects of Mcl-1 are generally short lived compared with those of Bcl-2 and are not obvious in some transfectants. To further explore the effects of this gene, mice were produced that expressed Mcl-1 as a transgene in hematolymphoid tissues. The Mcl-1 transgene was found to cause moderate viability enhancement in a wide range of hematopoietic cell types, including lymphoid (B and T) as well as myeloid cells at both immature and mature stages of differentiation. However, enhanced hematopoietic capacity in transgenic bone marrow and spleen was not reflected in any change in pool sizes in the peripheral blood. In addition, among transgenic cells, mature T cells remained long lived compared with B cells and macrophages could live longer than either of these. Interestingly, when hematopoietic cells were maintained in tissue culture in the presence of interleukin-3, Mcl-1 enhanced the probability of outgrowth of continuously proliferating myeloid cell lines. Thus, Mcl-1 transgenic cells remained subject to normal in vivo homeostatic mechanisms controlling viable cell number, but these constraints could be overridden under specific conditions in vitro. Within the organism, Bcl-2 family members may act at “viability gates” along the differentiation continuum, functioning as part of a system for controlled hematopoietic cell amplification. Enforced expression of even a moderate viability-promoting member of this family such as Mcl-1, within a conducive intra- and extracellular environment in isolation from normal homeostatic constraints, can substantially increase the probability of cell immortalization. © 1998 by The American Society of Hematology.

The microenvironment differentially impairs passive and active immunotherapy in chronic lymphocytic leukaemia – CXCR4 antagonists as potential adjuvants for monoclonal antibodies

“…Accordingly, the inhibition of this pathway may explain the efficacy of CXCR4 antagonists in this setting. In line with our observations, Mcl‐1 has been reported to mediate apoptosis resistance to fludarabine and rituximab in vivo (Zhou et al, 1998; Johnston et al , 2004; Pepper et al, 2008; Awan et al, 2009), and downregulation of Mcl‐1 by siRNA enhances RIT‐mediated apoptosis in vitro (Hussain et al , 2007).…”

“…We and others observed upregulation of the anti‐apoptotic Bcl‐2 family member Mcl‐1 upon stromal cell contact (Balakrishnan et al , 2009). The potential role of Mcl‐1 as an oncogene in lymphoid malignancies was confirmed in transgenic mouse models in which animals with deregulated expression of Mcl‐1 eventually developed widely disseminated B‐cell lymphoma (Zhou et al , 1998). Interestingly, in CLL, stromal cell contact also upregulates Akt activation (Edelmann et al , 2008), an effect abrogated by CXCR4 antagonists (Fig 1C).…”

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

“…Expression of MCL‐1 was also observed to be present and mostly stable throughout hematopoiesis, especially during B and T lymphocyte development from hematopoietic stem cells, which is followed by common lymphoid progenitor . This phenomenon was also supported by the data obtained from MCL‐1‐overexpressing transgenic mice, which demonstrated splenomegaly with increased hematopoiesis and increased leukocyte survival . More importantly for the subject of this review, different types of B‐cell lymphomas was also a consequence observed in these MCL‐1‐overexpressing transgenic mice .…”

Deciphering the rules of programmed cell death to improve therapy of cancer and other diseases

“…Studies using transgenic and gene‐knockout mice have greatly illuminated the biological functions of Bcl‐2 family members. Demonstrating the role of the guardians, overexpression in lymphoid and other haemopoietic cells of Bcl‐2 (McDonnell et al , 1989; Strasser et al , 1990b, 1991a, 1991b; Sentman et al , 1991), Bcl‐x L (Grillot et al , 1995), Mcl‐1 (Zhou et al , 1998; Campbell et al , 2010) or A1 (Chuang et al , 2002) protects against diverse cytotoxic signals, both physiological (e.g. cytokine deprivation) or imposed (e.g.…”