The c-myc oncogene perturbs B lymphocyte development in Eμ-myc transgenic mice

doi:10.1016/0092-8674(86)90361-2

Cell

Volume 47, Issue 1, 10 October 1986, Pages 11-18

https://doi.org/10.1016/0092-8674(86)90361-2 Get rights and content

Abstract

Transgenic mice bearing a c-myc oncogene subjugated to the lymphoid-specific immunoglobulin heavy chain enhancer (Eμ) develop clonal B lymphoid malignancies, but most young Eμ-myc mice lack malignant clones. Their prelymphomatous state has allowed us to examine how constitutive c-myc expression influences B cell development. We find that early stages are overrepresented, even before birth. Pre-B cells of polyclonal origin increase greatly, while B cells develop in reduced number. Both the pre-B and the B cells appear to be in an active state, since they are larger than normal and a greater fraction are in the cell cycle. Enforced myc expression has thus favored proliferation over maturation. Hence, a normal function of c-myc may be to regulate differentiation as well as to promote cell cycling.

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Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc–driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc–driven B-cell lymphoma, whereas PARP-1 deficiency accelerates lymphomagenesis in the Eμ-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic Eμ-Myc B cells, resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc–driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1 deficiency induces a proinflammatory response and an increase in regulatory T cells, likely contributing to immune escape of B-cell lymphoma, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc–driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centered therapeutic strategies, with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc–driven tumors.
Development and survival of MYC-driven lymphomas require the MYC antagonist MNT to curb MYC-induced apoptosis
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Deregulated overexpression of MYC is implicated in the development and malignant progression of most (∼70%) human tumors. MYC drives cell growth and proliferation, but also, at high levels, promotes apoptosis. Here, we report that the proliferative capacity of MYC-driven normal and neoplastic B lymphoid cells depends on MNT, a MYC-related transcriptional repressor. Our genetic data establish that MNT synergizes with MYC by suppressing MYC-driven apoptosis, and that it does so primarily by reducing the level of pro-apoptotic BIM. In Eμ-Myc mice, which model the MYC/IGH chromosome translocation in Burkitt's lymphoma, homozygous Mnt deletion greatly reduced lymphoma incidence by enhancing apoptosis and markedly decreasing premalignant B lymphoid cell populations. Strikingly, by inducing Mnt deletion within transplanted fully malignant Eμ-Myc lymphoma cells, we significantly extended transplant recipient survival. The dependency of lymphomas on MNT for survival suggests that drugs inhibiting MNT could significantly boost therapy of MYC-driven tumors by enhancing intrinsic MYC-driven apoptosis.
MicroRNA dysregulation and multi-targeted therapy for cancer treatment
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We established that loss of miR-15a/16–1 genes on chromosome 13q14 is the most common alteration in Chronic Lymphocytic Leukemia (CLL) and that miR-15/16 are crucial negative regulator of BCL-2, an antiapoptotic gene overexpressed in most CLLs and in many other malignancies. We have also shown that miR-15/16 target ROR1, a cell surface receptor for Wnt5a which can enhance growth/survival of CLL cells. Interestingly, ROR1 is expressed by many cancers, but not by normal adult tissues. Moreover, Venetoclax, the anti-Bcl-2 drug, and Cirmtuzumab, the monoclonal antibody against ROR1, are synergistic in killing CLL cells.
Since an additional miR-15/16 locus exists on chromosome 3q25 (miR-15b/16–2), we generated a knocked out mouse model to study its the role in cancer. We observed that the KO mice developed predominantly CLL. Thus, we generated a double knock out mouse model where both miR-15/16 loci were deleted. Surprisingly we observed that 77% of double KO mice developed Acute Myeloid Leukemia (AML). Based on these evidences, we anticipate that also AMLs with low miR-15/16 expression, overexpression of BCL2 and expression of ROR1, would show an excellent response to a combination therapy with Venetoclax and Cirmtuzumab, since both drugs target the same malignant cells that have lost miR-15/16.
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Citation Excerpt :
PIM kinases are often considered ‘weak’ oncogenes and seem to be mostly effective in modulating the activity of ‘stronger’ oncogenes, such as MYC. For example, the EμMYC model of lymphoma gives rise to rapidly progressing, lethal lymphoid malignancy (Harris et al., 1988; Langdon et al., 1986) but EμPIM mice have comparably longer disease latency (Breuer et al., 1989; van Lohuizen et al., 1989). As reported for PIM1 in EμMYC lymphoma (Breuer et al., 1991), PIM2 also cooperates with MYC to accelerate lymphomagenesis and lethal disease (Allen et al., 1997).
The PIM kinases are proto-oncogenes which have been shown to facilitate cell survival and proliferation to drive malignancy and resistance post-therapy. They are able to suppress cell death signals, sustain PI3K/AKT/mTORC1 pathway activity and regulate the MYC oncogenic program. Recent work has revealed PIM kinase essentiality for advanced tumour maintenance and described tumour sensitivity to small molecule inhibitors targeting PIM kinase in multiple malignancies.
Mutant mice lacking alternatively spliced p53 isoforms unveil Ackr4 as a male-specific prognostic factor in Myc-driven B-cell lymphomas
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Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis
2023, Cell Death and Differentiation

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Abstract

References (30)

Induction of antibody formation in mouse bone marrow

Activation of cellular oncogenes in hemopoietic cells by chromosome translocations

Adv. Cancer Res.

Introduction of a μ immunoglobulin gene into the mouse germ line: specific expression in lymphoid cells and synthesis of functional antibody

Cell

Cell-specific regulation of the c-myc gene by lymphocyte mitogens and plateletderived growth factor

Cell

Myc/lg juxtaposition by chromosomal translocations: some new insights, puzzles and paradoxes

Immunol. Today

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J. Immunol. Methods

Detection of specific sequences among DNA fragments separated by gel electrophoresis

J. Mol. Biol.

Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes

Cell

The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice

Nature

c-myc-induced lymphomagenesis in transgenic mice and the role of Pvt-1 locus in lymphoid neoplasia

Curr. Topics Microbiol. Immunol.

Regulation of genome rearrangement events during lymphocyte differentiation

Immunol. Rev.

Functional role for c-myc in mitogenic response to platelet-derived growth factor

Nature

Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs

Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development

Immunol. Rev.

Constitutive c-myc oncogene expression blocks mouse erythroleukaemia cell differentiation but not commitment

Nature

Cited by (349)

Distinct roles for PARP-1 and PARP-2 in c-Myc–driven B-cell lymphoma in mice

Development and survival of MYC-driven lymphomas require the MYC antagonist MNT to curb MYC-induced apoptosis

MicroRNA dysregulation and multi-targeted therapy for cancer treatment

PIM activity in tumours: A key node of therapy resistance

Mutant mice lacking alternatively spliced p53 isoforms unveil Ackr4 as a male-specific prognostic factor in Myc-driven B-cell lymphomas

Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis

Cell

ArticleThe c-myc oncogene perturbs B lymphocyte development in Eμ-myc transgenic mice

Abstract

Adv. Cancer Res.

Cell

Cell

Immunol. Today

J. Immunol. Methods

J. Mol. Biol.

Cell

The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice

Nature

c-myc-induced lymphomagenesis in transgenic mice and the role of Pvt-1 locus in lymphoid neoplasia

Curr. Topics Microbiol. Immunol.

Regulation of genome rearrangement events during lymphocyte differentiation

Immunol. Rev.

Functional role for c-myc in mitogenic response to platelet-derived growth factor

Nature

Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs

Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development

Immunol. Rev.

Constitutive c-myc oncogene expression blocks mouse erythroleukaemia cell differentiation but not commitment

Nature

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The c-myc oncogene perturbs B lymphocyte development in Eμ-myc transgenic mice