Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

Jabbour, Elias; Ottmann, Oliver G.; Deininger, Michael W.; Hochhaus, Andreas

doi:10.3324/haematol.2013.087171

Cited by 47 publications

(41 citation statements)

References 98 publications

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“…Akt is a major effector of PI3K signaling, critical to survival, proliferation, metabolism and therefore to hematological malignancies, with potential clinical utility for leukemia treatment. 48,51 Segregation of AC133 and CD50 marks HSPC polarity, 2,3,9 which requires active PI3K. 9 Thus, we propose that polarized distribution of AC133 and CD50 on NCL-HSPC cells (Figure 1b) to a uropod-like structure is associated with increased cellular PI3K/Akt activity.…”

Section: Mobilized Pb Hspcsmentioning

confidence: 91%

Control of AC133/CD133 and impact on human hematopoietic progenitor cells through nucleolin

et al. 2015

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AC133 is a prominent surface marker of CD34+ and CD34- hematopoietic stem/progenitor cell (HSPC) subsets. AC133+ HSPCs contain high progenitor cell activity and are capable of hematopoietic reconstitution. Furthermore, AC133 is used for prospective isolation of tumor-initiating cells in several hematological malignancies. Nucleolin is a multifunctional factor of growing and cancer cells, which is aberrantly active in certain hematological neoplasms, and serves as a candidate molecular target for cancer therapy. Nucleolin is involved in gene transcription and RNA metabolism and is prevalently expressed in HSPCs, as opposed to differentiated hematopoietic tissue. The present study dissects nucleolin-mediated activation of surface AC133 and its cognate gene CD133, via specific interaction of nucleolin with the tissue-dependent CD133 promoter P1, as a mechanism that crucially contributes to AC133 expression in CD34+ HSPCs. In mobilized peripheral blood (MPB)-derived HSPCs, nucleolin elevates colony-forming unit (CFU) frequencies and enriches granulocyte-macrophage CFUs. Furthermore, nucleolin amplifies long-term culture-initiating cells and also promotes long-term, cytokine-dependent maintenance of hematopoietic progenitor cells. Active β-catenin, active Akt and Bcl-2 levels in MPB-derived HSPCs are nucleolin-dependent, and effects of nucleolin on these cells partially rely on β-catenin activity. The study provides new insights into molecular network relevant to stem/progenitor cells in normal and malignant hematopoiesis.

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Section: Mobilized Pb Hspcsmentioning

confidence: 91%

Control of AC133/CD133 and impact on human hematopoietic progenitor cells through nucleolin

et al. 2015

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“…37 Based on extensive preclinical data, other dual inhibitors are in clinical development. [38][39][40] …”

Section: Pi3k (Phosphatidylinositol 3'-kinase)mentioning

confidence: 98%

Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

Carneiro

Kaplan

Altman

et al. 2015

Cancer Biology & Therapy

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An accumulating understanding of the complex pathogenesis of acute myeloid leukemia (AML) continues to lead to promising therapeutic approaches. Among the key aberrant intracellular signaling pathways involved in AML, the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) axis is of major interest. This axis modulates a wide array of critical cellular functions, including proliferation, metabolism, and survival. Pharmacologic inhibitors of components of this pathway have been developed over the past decade, but none has an established role in the treatment of AML. This review will discuss the preclinical data and clinical results driving ongoing attempts to exploit the PI3K/AKT/mTOR pathway in patients with AML and address issues related to negative feedback loops that account for leukemic cell survival. Targeting the PI3K/AKT/mTOR pathway is of high interest for the treatment of AML, but combination therapies with other targeted agents may be needed to block negative feedback loops in leukemia cells.

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“…Increased levels of PI3Kα was observed in resistant primary MCL cells, and at relapse compared to baseline [42]. Pan PI3K inhibitors (BKM120, XL147, BAY 80-6946, and GDC-0941) and the dual PI3Kγ/δ inhibitor (IPI-145) recently entered clinical testing in patients with hematological malignancies [43, 44]. So it will be interesting to see whether these drugs lead to more sustained and durable responses.…”

Section: The Role Of Bcr Signaling and The Tissue Microenvironment Inmentioning

confidence: 99%

Do mantle cell lymphomas have an ‘Achilles heel’?

Saba

Wiestner

2014

Current Opinion in Hematology

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Purpose of review Mantle cell lymphoma (MCL) is a mature B-cell malignancy that continues to have a high mortality rate. In this manuscript we discuss key pathogenic pathways in MCL biology and their possible therapeutic targeting. Recent findings In addition to Cyclin-D1 the transcription factor SOX-11 emerged as a common characteristic of MCL. Genomic studies have identified a number of recurrently mutated genes; in order of descending frequency these include ATM, CCND1, UBR5, TP53, BIRC3, NOTCH1/2 and TRAF2. However, no clear oncogenic driver has been identified. In contrast, several observations indicate that MCL cells are antigen-experienced cells and that the tumor microenvironment and B-cell receptor engagement are important. This is underscored by the impressive clinical responses achieved with the BTK inhibitor ibrutinib. Recently identified activating mutations in the non-canonical NF-κB pathway could give rise to ibrutinib resistance. PARP and aurora kinase inhibitors may be synthetic lethal with the common aberrations in DNA damage pathways found in MCL. Also, ABT-199, a potent and selective inhibitor of BCL-2 has promising activity in early studies. Summary MCL is a heterogeneous disease and no single Achilles heel has been identified. Nevertheless, genomic, molecular, and clinical studies have revealed vulnerabilities that can be exploited for effective therapy.

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Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

Cited by 47 publications

References 98 publications

Control of AC133/CD133 and impact on human hematopoietic progenitor cells through nucleolin

Control of AC133/CD133 and impact on human hematopoietic progenitor cells through nucleolin

Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

Do mantle cell lymphomas have an ‘Achilles heel’?

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