Inhibition of the Intrinsic but Not the Extrinsic Apoptosis Pathway Accelerates and Drives Myc-Driven Tumorigenesis Towards Acute Myeloid Leukemia

Högstrand, Kari; Hejll, Eduar; Sander, Birgitta; Rozell, Björn; Larsson, Lars‐Gunnar; Grandien, Alf

doi:10.1371/journal.pone.0031366

Cited by 20 publications

(20 citation statements)

References 46 publications

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“…The authors adhere to the “Guidelines for the use of flow cytometry and cell sorting in immunological studies” . Immunochemistry was performed as described . The following Abs were used: Anti‐CD3 (clone SP7, Labvision, Fremont, CA), anti‐CD45R/B220 (clone RA3‐6B2) and anti‐PAX5 (Santa Cruz Biotechnology, Inc. Santa Cruz, CA).…”

Section: Methodsmentioning

confidence: 99%

MYC‐driven malignant transformation of mature murine B cells requires inhibition of both intrinsic apoptosis and p53 activity

Högstrand

Grandien

2018

Eur J Immunol

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Increased expression of the oncogene MYC is a common feature of many B‐cell malignancies, however MYC overexpression by itself is not sufficient for transformation, and additional genetic events are required, although the exact nature of these remains unknown. In patients and in transgenic mouse models, oncogenic transformation may occur in B cells at various differentiation stages interacting with complex microenvironments. B‐cell oncogenesis often occurs after prolonged periods of time, making it difficult to accurately identify the genetic events required for transformation. An in vitro system, where malignant transformation of primary B cells could be analyzed, would facilitate the identification of genetic events required for transformation. Here, we describe such a system and show that primary murine B cells rapidly become transformed upon forced expression of MYC, in conjunction with simultaneous inhibition of the ARF/p53 axis via overexpression of BMI1, as well as through downregulation of p19ARF or expression of a dominant‐negative p53 and suppression of intrinsic apoptosis through overexpression of BCLXL or MCL1. Established tumor cells remained addicted to expression of the lymphoma‐inducing genes. In mice, transformed cells rapidly established fatal B‐cell lymphomas. Our results suggest that transformation of normal mature B cells into lymphomas can occur as a consequence of three defined events.

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Section: Methodsmentioning

confidence: 99%

MYC‐driven malignant transformation of mature murine B cells requires inhibition of both intrinsic apoptosis and p53 activity

Högstrand

Grandien

2018

Eur J Immunol

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“…The Bcl-2 family proteins operate as nodal points at the convergence of multiple pathways (106), and their central role in triggering the final common pathway of apoptosis, characterized by caspase activation, makes them particularly attractive drug targets (67). Multiple studies have implicated the role of Bcl-2 family proteins in AML pathogenesis (20,42,50), prognosis (27,48,131), and resistance to chemotherapy (11,66,69,118). Small-molecule "BH3-mimetics" that inhibit the antiapoptotic functions of Bcl-2 and Bcl-xL have, therefore, been developed (91,121,129).…”

Section: Bcl-2 Family Of Pro-and Antiapoptotic Proteinsmentioning

confidence: 99%

Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML

Vachhani

Bose

Rahmani

et al. 2014

Physiological Genomics

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Acute myeloid leukemia (AML) continues to represent an area of critical unmet need with respect to new and effective targeted therapies. The Bcl-2 family of pro- and antiapoptotic proteins stands at the crossroads of cellular survival and death, and the expression of and interactions between these proteins determine tumor cell fate. Malignant cells, which are often primed for apoptosis, are particularly vulnerable to the simultaneous disruption of cooperative survival signaling pathways. Indeed, the single agent activity of agents such as mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase kinase (MEK) inhibitors in AML has been modest. Much work in recent years has focused on strategies to enhance the therapeutic potential of the bona fide BH3-mimetic, ABT-737, which inhibits B-cell lymphoma 2 (Bcl-2) and Bcl-xL. Most of these strategies target Mcl-1, an antiapoptotic protein not inhibited by ABT-737. The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways are central to the growth, proliferation, and survival of AML cells, and there is much interest currently in pharmacologically interrupting these pathways. Dual inhibitors of PI3K and mTOR overcome some intrinsic disadvantages of rapamycin and its derivatives, which selectively inhibit mTOR. In this review, we discuss why combining dual PI3K/mTOR blockade with inhibition of Bcl-2 and Bcl-xL, by virtue of allowing coordinate inhibition of three mutually synergistic pathways in AML cells, may be a particularly attractive therapeutic strategy in AML, the success of which may be predicted for by basal Akt activation.

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“…c-Myc is one of the direct target gene products of Stat-5 which cross-talks with Akt/mTOR and directly targets Bcl-2 and Bcl-xL[6], and the combined targeting of Akt/mTOR using rapamycin and of Bcl-2 and Bcl-xL using ABT-737 has been shown to suppress the survival of Stat-5-dependent myeloproliferative neoplasms[35]. Given the proposed importance of c-Myc in AML biology[36], further studies dissecting the role of c-Myc in ABT-737 resistance may be informative.…”

Section: Discussionmentioning

confidence: 99%

PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment

et al. 2013

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Both phosphatidylinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling and antiapoptotic Bcl-2 family members are critical for survival of acute myeloid leukemia (AML) cells. Here we demonstrate the antileukemic effects of simultaneous inhibition of PI3K by the selective class I PI3K inhibitor GDC-0941 and of Bcl-2 family members by the BH3 mimetic ABT-737 in the context of the bone marrow microenvironment, where hypoxia and interactions with bone marrow stromal cells promote AML cell survival and chemoresistance. The combination of GDC-0941 and ABT-737 profoundly downregulated antiapoptotic Mcl-1 expression levels, activated BAX, and induced mitochondrial apoptosis in AML cells co-cultured with bone marrow stromal cells under hypoxic conditions. Hypoxia caused degradation of Mcl-1 and rendered Mcl-1-overexpressing OCI-AML3 cells sensitive to ABT-737. Our findings suggest that pharmacologic PI3K inhibition by GDC-0941 enhances ABT-737–induced leukemia cell death even under the protective conditions afforded by the bone marrow microenvironment.

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Inhibition of the Intrinsic but Not the Extrinsic Apoptosis Pathway Accelerates and Drives Myc-Driven Tumorigenesis Towards Acute Myeloid Leukemia

Cited by 20 publications

References 46 publications

MYC‐driven malignant transformation of mature murine B cells requires inhibition of both intrinsic apoptosis and p53 activity

MYC‐driven malignant transformation of mature murine B cells requires inhibition of both intrinsic apoptosis and p53 activity

Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML

PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment

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