Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Kumari, Ashu; Brendel, Cornelia; Hochhaus, Andreas; Neubauer, Andreas; Burchert, Andreas

doi:10.1182/blood-2010-08-303495

Cited by 80 publications

(93 citation statements)

References 48 publications

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“…Currently, qRT-PCR is used to measure treatment response; however, a recent study demonstrated that low expression levels of BCR-ABL in a stem cell population are associated with resistance to imatinib. 29 These cells would be difficult to detect using qRT-PCR and therefore alternative methods to monitor residual disease may be useful. One possibility is the measurement of BCR-ABL fusion junctions from genomic DNA, an approach that is technically demanding and labor intensive because the genomic breakpoints need to be characterized for each patient and individual detection assays designed and validated.…”

Section: Towards the Path To A Curementioning

confidence: 99%

Standardized definitions of molecular response in chronic myeloid leukemia

et al. 2012

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Section: Towards the Path To A Curementioning

confidence: 99%

Standardized definitions of molecular response in chronic myeloid leukemia

et al. 2012

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“…Recently, it has become clear that while differentiated CML cells are dependent on BCR-ABL1 activity for their survival and therefore remain sensitive to kinase inhibition, CML stem cells do not rely on its activity and persist despite the effective inhibition of the BCR-ABL1 by TKIs [18][19][20]. These studies clearly highlight the need for targeting the BCR-ABL1-independent, alternative mechanisms that protect and sustain CML stem cells to develop curative therapies for this hematologic malignancy.…”

Section: Chronic Myeloid Leukemiamentioning

confidence: 99%

Stem cell maintenance and disease progression in chronic myeloid leukemia

Ito

2013

Int J Hematol

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Chronic myeloid leukemia (CML) is a cancer of blood cells driven by the BCR-ABL1 oncogenic protein tyrosine kinase, which is the product of a reciprocal chromosomal translocation known as the Philadelphia chromosome. Discovery of tyrosine kinase inhibitors targeting the BCR-ABL1 kinase revolutionized CML therapy, but these drugs are unable to eradicate the disease due to the presence of a drug-insensitive stem cell population that sustains continued growth of the malignant cells. Resistance to therapies also increases the risk of relapse and disease progression to a more advanced phase. This review discusses emerging issues in CML research, and describes recent progress in elucidating the mechanisms of CML stem cell maintenance and disease progression.

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“…42 Furthermore, quiescent LSCs that are not effectively targeted by TKIs can persist in the bone marrow. 41 Klejman et al showed that PI3K inhibition enhanced the activity of imatinib against CML cell lines. 43 Notably, BCR-ABL1-independent activation of the PI3K signaling pathway has been reported in TKI-resistant CML cell lines.…”

Section: Chronic Myelogenous Leukemiamentioning

confidence: 99%

“…41 The constitutively activated BCR-ABL1 tyrosine kinase is the main oncogenic driver in the pathogenesis of CML, leading to downstream activation of the PI3K signaling pathway. Expression of p85α is critical for the proliferation and survival of BCR-ABL1-expressing CML cells.…”

Section: Chronic Myelogenous Leukemiamentioning

confidence: 99%

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

et al. 2014

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The phosphoinositide 3-kinase pathway represents an important anticancer target because it has been implicated in cancer cell growth, survival, and motility. Recent studies show that PI3K may also play a role in the development of resistance to currently available therapies. In a broad range of cancers, various components of the phosphoinositide 3-kinase signaling axis are genetically modified, and the pathway can be activated through many different mechanisms. The frequency of genetic alterations in the phosphoinositide 3-kinase pathway, coupled with the impact in oncogenesis and disease progression, make this signaling axis an attractive target in anticancer therapy. A better understanding of the critical function of the phosphoinositide 3-kinase pathway in leukemias and lymphomas has led to the clinical evaluation of novel rationally designed inhibitors in this setting. Three main categories of phosphoinositide 3-kinase inhibitors have been developed so far: agents that target phosphoinositide 3-kinase and mammalian target of rapamycin (dual inhibitors), pan-phosphoinositide 3-kinase inhibitors that target all class I isoforms, and isoform-specific inhibitors that selectively target the α, -β, -g, or -d isoforms. Emerging data highlight the promise of phosphoinositide 3-kinase inhibitors in combination with other therapies for the treatment of patients with hematologic malignancies. Further evaluation of phosphoinositide 3-kinase inhibitors in first-line or subsequent regimens may improve clinical outcomes. This article reviews the role of phosphoinositide 3-kinase signaling in hematologic malignancies and the potential clinical utility of inhibitors that target this pathway. ABSTRACTE. Jabbour et al. 8 haematologica | 2014; 99 (1) where it activates the AKT serine/threonine kinase by phosphorylating the threonine 308 residue (Figure 1). In turn, AKT phosphorylates many downstream substrates, including forkhead box protein O (FOXO), glycogen synthase kinase-3 (GSK-3), and Bcl-2 associated death promoter (BAD). AKT-mediated phosphorylation also inhibits the proline-rich AKT substrate of 40 kDa (PRAS40) and tuberous sclerosis complex 2 (TSC2), thereby activating mTOR complex 1 (mTORC1). mTORC1 consists of mTOR, mTOR-associated protein LST8 homolog (mLST8), regulatory associated protein of mTOR (RAPTOR), DEP domain TOR-binding protein (DEPTOR), and PRAS40. Activated mTORC1 stimulates protein synthesis by phosphorylating the ribosomal kinase proteins S6K1 (p70S6K/p85S6K) and S6K2 (p54S6K), and the eukaryotic initiation factor 4E-binding proteins (4E-BP1, 4E-BP2, and 4E-BP3). 17,18 mTORC2 is physiologically distinct from mTORC1 and consists of mTOR, mLST8, DEPTOR, rapamycin-insensitive companion of mTOR (RICTOR), protein observed with RIC-TOR (PROTOR), and mammalian stress-activated protein kinase interaction protein 1 (mSIN1). Unlike mTORC1, mTORC2 is considered rapamycin-insensitive because its inhibition requires prolonged drug exposure. While its function is not fully elucidated, mTORC2 is known to phosphoryla...

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Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib

Cited by 80 publications

References 48 publications

Standardized definitions of molecular response in chronic myeloid leukemia

Standardized definitions of molecular response in chronic myeloid leukemia

Stem cell maintenance and disease progression in chronic myeloid leukemia

Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies

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