Increased Expression of Bcl-xL and c-Myc Is Associated with Transformation by Abelson Murine Leukemia Virus

Noronha, E. Jacintha; Sterling, Karen Hinrichs; Calame, Kathryn

doi:10.1074/jbc.m306629200

Cited by 9 publications

(4 citation statements)

References 43 publications

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“…Given the different expression profiles of cyclin D1, cyclin E, cdk4, and p27 between S4 and S4C2-1, we reasoned that c-myc mRNA levels might also differ in these two cell types. The c-myc transcript was reduced in S4 cells cultured at 39°C, as compared with cells maintained at 33°C, which is consistent with previous reports (24,25). Interestingly, the level of c-myc mRNA remained low in S4 cells after their return to 33°C, and eventually reached its basal level 4 days later (Fig.…”

Section: Figuresupporting

confidence: 92%

Growth, Differentiation, and Malignant Transformation of Pre-B Cells Mediated by Inducible Activation of v-Abl Oncogene

Jacobsen

Ananieva

Brown

et al. 2006

The Journal of Immunology

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The nonreceptor tyrosine kinase, encoded by the v-Abl oncogene of Abelson murine leukemia virus induces transformation of progenitor B cells. The v-Abl oncogene promotes cell cycle progression and inhibits pre-B cell differentiation. The temperature-sensitive form of Abelson murine leukemia virus offers a reversible model to study the role of v-Abl in regulating growth and differentiation. Inactivation of v-Abl elevates p27 and Foxo3a levels and activates NF-κB/Rel, which leads to G1 arrest and induction of Ig L chain gene rearrangement, respectively. In turn, v-Abl reactivation reduces p27 and Foxo3a levels, thus permitting G1-arrested cells to reenter the cell cycle. However, the cell lines derived from SCID mice that are defective in the catalytic subunit of DNA-dependent protein kinase retain elevated levels of p27 and Foxo3a proteins despite reactivation of v-Abl. Consequently, these cells are locked in the G1 phase for an extended period of time. The few cells that manage to bypass the G1 arrest become tumorigenic and fail to undergo pre-B cell differentiation induced by v-Abl inactivation. Deregulation of p27, Foxo3a, c-myc, and NF-κB/Rel was found to be associated with the malignant transformation of SCID temperature-sensitive form of Abelson murine leukemia virus pre-B cells.

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Section: Figuresupporting

confidence: 92%

Growth, Differentiation, and Malignant Transformation of Pre-B Cells Mediated by Inducible Activation of v-Abl Oncogene

Jacobsen

Ananieva

Brown

et al. 2006

The Journal of Immunology

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“…The role of BCL-XL in cell survival, 82,83 malignant transformation, 84,85 and chemoresistance, 86,87 specifically in context of doxorubicin in leukemia and other malignancies, 59,[88][89][90] is well-established. Targeting apoptosis is an attractive therapeutic approach for both hematological and solid tumor malignancies.…”

Section: Discussionmentioning

confidence: 99%

IKAROS and CK2 regulate expression of BCL-XL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia

Song

Ding

et al. 2020

Blood

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High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the IKAROS (encoded by the IKZF1 gene) tumor suppressor. Here, we report that IKAROS regulates expression of the BCL2L1 gene (encodes the BCL-XL protein) in human B-ALL. Gain-of-function and loss-of-function experiments demonstrate that IKAROS binds to the BCL2L1 promoter, recruits histone deacetylase HDAC1, and represses BCL2L1 expression via chromatin remodeling. In leukemia, IKAROS' function is impaired by oncogenic Casein Kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces IKAROS binding and recruitment of HDAC1 to the BCL2L1 promoter. This results in a loss of IKAROS-mediated repression of BCL2L1 and increased expression of BCL-XL. Increased expression of BCL-XL and/or CK2, as well as reduced IKAROS expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, increases binding of IKAROS to the BCL2L1 promoter and enhances IKAROS-mediated repression of BCL2L1 in B-ALL. Treatment with CX-4945 increases sensitivity to doxorubicin in B-ALL, and reverses resistance to doxorubicin in multi-drug resistant B-ALL. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia. These data lay the groundwork for clinical testing of a rationally-designed, targeted therapy that combines the CK2 inhibitor, CX-4945, with doxorubicin for the treatment of hematopoietic malignancies.

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“…Such an idea is countered by literature indicating that Myc, a gene known to be upregulated in expression by v-Abl in at least some cell types (22,47,49), can induce Arf expression (48). To determine how expression of these genes is affected by v-Abl expression in pre-B cells, bone marrow cells were infected with a virus that expresses v-Abl and GFP and the infected cells were recovered by flow cytometry 6, 8, and 10 days postinfection.…”

Section: Fig 1 Expression Of P19mentioning

confidence: 90%

“…For example, increased expression of c-Myc, known to induce upregulation of Arf expression (48), has been reported to occur rapidly in response to v-Abl expression (22,47,49). However, even though v-Abl expression occurs very soon after virus integration, previous studies have first detected p19 Arf expression about 2 weeks postinfection, coincident with the onset of the crisis phase of transformation (26).…”

Section: Although P19mentioning

confidence: 99%

Changes in p19 ^Arf Localization Accompany Apoptotic Crisis during Pre-B-Cell Transformation by Abelson Murine Leukemia Virus

Zimmerman¹,

Rosenberg

2008

J Virol

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Transformation by Abelson murine leukemia virus (Ab-MLV) is a multistep process in which growthstimulatory signals from the v-Abl oncoprotein and growth-suppressive signals from the p19Arf -p53 tumor suppressor pathway oppose each other and influence the outcome of infection. The process involves a proliferative phase during which highly viable primary transformants expand, followed by a period of marked apoptosis (called "crisis") that is dependent on the presence of p19Arf and p53; rare cells that survive this phase emerge as fully transformed and malignant. To understand the way in which v-Abl expression affects p19Arf expression, we examined changes in expression of Arf during all stages of Ab-MLV transformation process. As is consistent with the ability of v-Abl to stimulate Myc, a transcription factor known to induce p19Arf , Myc and Arf are induced soon after infection and p19 Arf is expressed. At these early time points, the infected cells remain highly viable. The onset of crisis is marked by an increase in p19Arf expression and a change in localization of the protein from the nucleoplasm to the nucleolus. These data together suggest that the localization and expression levels of p19Arf modulate the effects of the protein during oncogenesis and reveal that the p19Arf -mediated response is subject to multiple layers of regulation that influence its function during Ab-MLV-mediated transformation.

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Increased Expression of Bcl-xL and c-Myc Is Associated with Transformation by Abelson Murine Leukemia Virus

Cited by 9 publications

References 43 publications

Growth, Differentiation, and Malignant Transformation of Pre-B Cells Mediated by Inducible Activation of v-Abl Oncogene

Growth, Differentiation, and Malignant Transformation of Pre-B Cells Mediated by Inducible Activation of v-Abl Oncogene

IKAROS and CK2 regulate expression of BCL-XL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia

Changes in p19 ^Arf Localization Accompany Apoptotic Crisis during Pre-B-Cell Transformation by Abelson Murine Leukemia Virus

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Increased Expression of Bcl-xL and c-Myc Is Associated with Transformation by Abelson Murine Leukemia Virus

Cited by 9 publications

References 43 publications

Growth, Differentiation, and Malignant Transformation of Pre-B Cells Mediated by Inducible Activation of v-Abl Oncogene

Growth, Differentiation, and Malignant Transformation of Pre-B Cells Mediated by Inducible Activation of v-Abl Oncogene

IKAROS and CK2 regulate expression of BCL-XL and chemosensitivity in high-risk B-cell acute lymphoblastic leukemia

Changes in p19 Arf Localization Accompany Apoptotic Crisis during Pre-B-Cell Transformation by Abelson Murine Leukemia Virus

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Changes in p19 ^Arf Localization Accompany Apoptotic Crisis during Pre-B-Cell Transformation by Abelson Murine Leukemia Virus