Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia

Hajj, Hiba El; El-Sabban, Marwan; Hasegawa, Hideki; Zaatari, Ghazi; Ablain, Julien; Saab, Shahrazad; Janin, Anne; Mahfouz, Rami; Nasr, Rihab; Kfoury, Youmna; Nicot, Christophe; Hermine, Olivier; Hall, William W.; Thé, Hugues de; Bazarbachi, Ali

doi:10.1084/jem.20101095

Cited by 84 publications

(121 citation statements)

References 28 publications

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“…Transplantation studies have demonstrated that even a very brief treatment, which does not impair in vivo tumor growth or proliferation, abrogates the capacity of leukemia to engraft in secondary hosts, provided that the proteasome is functioning (ref. 65; Fig. 3C ).…”

Section: Breast Cancermentioning

confidence: 91%

“…Yet, the oldest example of targeted therapy, is strongly suggested by the recent report that this combination can cure murine ATL derived from Tax-transgenic mice ( 65 ). Because the action of the IFN-α/arsenic combination is very specific to both HTLVI-infected human cells and Tax-driven murine leukemia, it is most likely that therapy-induced loss of the driving oncogene underlies responsiveness to therapy ( Fig.…”

Section: Breast Cancermentioning

confidence: 99%

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The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

et al. 2011

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Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases. Thus far, this approach has undoubtedly yielded significant clinical improvements, but has only rarely achieved cures. Other drugs, which selectively elicit proteasome-dependent degradation of oncoproteins, induce the loss of cancer cell self-renewal and promote cell differentiation and/or apoptosis. In acute promyelocytic leukemia, the cooperative degradation of PML/RARA by arsenic and retinoic acid cures most patients. In this condition and others, drug-induced proteolysis of oncoproteins is feasible and underlies improved clinical outcome. Several transcription factors, nuclear receptors, or fusion proteins driving cancer growth could be candidates for proteolysis-based drug-discovery programs. Summary: Some cancer therapies may degrade oncoproteins. Loss of the driver oncoprotein is associated with loss of cancer cell self-renewal. Leukemia- or sarcoma-associated fusion proteins are the best candidates for small-molecule screens aimed at initiating oncoprotein degradation. Cancer Discovery; 1(2). 117–27. ©2011 AACR.

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Section: Breast Cancermentioning

confidence: 91%

Section: Breast Cancermentioning

confidence: 99%

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

et al. 2011

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“…Importantly the combination of interferon and arsenic has unambiguous clinical benefit in HTLV-1 infected Adult T-Cell Leukemia (ATL) patients, where remissions can be achieved in the absence of chemotherapy. 122,123 Spinocerebellar ataxia (SCA1) is caused by accumulation of ataxin 1, a poly-glutamine stretch containing protein, which is degraded by the PML/SUMO/RNF4 system. 90 Interferon treatment can induce clearance of ataxin 7 from the brain in a PMLor SUMO-dependent manner, resulting in clinical benefit.…”

Section: The Interferon Connection and Medical Implicationsmentioning

confidence: 99%

PML nuclear bodies: Assembly and oxidative stress-sensitive sumoylation

Şahin¹,

Lallemand-Breitenbach²

2014

Nucleus

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“…IFNs induce a transient global polyubiquitination 61 , which could result from the hypersumoylation unravelled here. These findings have important therapeutic relevance, as IFNa promotes PML-and SUMO-dependent degradation of toxic proteins in the brain 62,63 or of the HTLV-I leukemia oncoprotein Tax 64 , with unambiguous clinical benefit 62,65,66 . Thus, similar to therapies based on manipulation of ubiquitin-dependent degradation 67,68 , this could pave the way to IFN-triggered, SUMO-based therapies promoting the proteolytic clearance of undesirable proteins 68 .…”

Section: Articlementioning

confidence: 99%

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

Şahin¹,

Ferhi²,

Carnec³

et al. 2014

Nat Commun

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Small ubiquitin-related modifier (SUMO) protein conjugation onto target proteins regulates multiple cellular functions, including defence against pathogens, stemness and senescence. SUMO1 peptides are limiting in quantity and are thus mainly conjugated to high-affinity targets. Conjugation of SUMO2/3 paralogues is primarily stress inducible and may initiate target degradation. Here we demonstrate that the expression of SUMO1/2/3 is dramatically enhanced by interferons through an miRNA-based mechanism involving the Lin28/let-7 axis, a master regulator of stemness. Normal haematopoietic progenitors indeed display much higher SUMO contents than their differentiated progeny. Critically, SUMOs contribute to the antiviral effects of interferons against HSV1 or HIV. Promyelocytic leukemia (PML) nuclear bodies are interferon-induced domains, which facilitate sumoylation of a subset of targets. Our findings thus identify an integrated interferon-responsive PML/SUMO pathway that impedes viral replication by enhancing SUMO conjugation and possibly also modifying the repertoire of targets. Interferon-enhanced post-translational modifications may be essential for senescence or stem cell self-renewal, and initiate SUMO-dependent proteolysis.

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Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia

Abstract: Treatment with a combination of interferon-α and arsenic trioxide ablates leukemia-initiating activity before reducing primary tumor bulk in a murine model of adult T cell leukemia.

Cited by 84 publications

References 28 publications

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

PML nuclear bodies: Assembly and oxidative stress-sensitive sumoylation

Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication

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