Emerging stem cell concepts for imatinib‐resistant chronic myeloid leukaemia: implications for the biology, management, and therapy of the disease

Valent, Peter

doi:10.1111/j.1365-2141.2008.07197.x

Cited by 59 publications

(143 citation statements)

References 198 publications

(340 reference statements)

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“…10,11,29 Hypoxia favors the self-renewal of normal hematopoietic stem cells, 30 and resistance to hypoxia is one of the defining features of leukemic stem cells. 31 Therefore, it may be more important to search for new antileukemic agents that target quiescent CML stem cells residing in the hypoxic BM milieu.…”

Section: Discussionmentioning

confidence: 99%

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

et al. 2010

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Abl tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib are ineffective against Bcr-Abl þ leukemic stem cells. Thus, the identification of novel agents that are effective in eradicating quiescent Bcr-Abl þ stem cells is needed to cure leukemias caused by Bcr-Abl þ cells. Human Bcr-Abl þ cells engrafted in the bone marrow of immunodeficient mice survive under severe hypoxia. We generated two hypoxia-adapted (HA)-Bcr-Abl þ sublines by selection in long-term hypoxic cultures (1.0% O 2 ). Interestingly, HA-Bcr-Abl þ cells exhibited stem cell-like characteristics, including more cells in a dormant, increase of side population fraction, higher b-catenin expression, resistance to Abl TKIs, and a higher transplantation efficiency. Compared with the respective parental cells, HA-Bcr-Abl þ cells had higher levels of protein and higher enzyme activity of glyoxalase-I (Glo-I), an enzyme that detoxifies methylglyoxal, a cytotoxic by-product of glycolysis. In contrast to Abl TKIs, Glo-I inhibitors were much more effective in killing HA-Bcr-Abl þ cells both in vitro and in vivo. These findings indicate that Glo-I is a novel molecular target for treatment of Bcr-Abl þ leukemias, and, in particular, Abl TKI-resistant quiescent Bcr-Abl þ leukemic cells that have acquired stem-like characteristics in the process of adapting to a hypoxic environment.

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Section: Discussionmentioning

confidence: 99%

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

et al. 2010

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“…19 CML stem cells display resistance against imatinib. 20 Previous studies have shown that tyrosine kinase inhibitor treatment in combination with inhibition of autophagy results in the eradication of CML stem cells. 2 To determine whether miR-30a-mediated autophagy is a potential survival mechanism for CML stem cells, we measured miR-30a expression in CD34 þ CML stem and progenitor cells.…”

Section: 3mentioning

confidence: 99%

Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells

et al. 2012

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A major advancement in the treatment of chronic myeloid leukemia (CML) has been the development of imatinib and other BCR-ABL tyrosine kinase inhibitors. MicroRNAs (miRNAs) are small RNA molecules that influence gene expression by post-transcriptional regulation of messenger RNA. It is not yet clear how miRNAs are able to regulate the effectiveness of imatinib in CML. Here, we show that imatinib markedly inhibits expression of miR-30a in human CML cells. miR-30a is a potent inhibitor of autophagy by downregulating Beclin 1 and ATG5 expression. miR-30a mimic or knockdown of autophagy genes (ATGs) such as Beclin 1 and ATG5 by short hairpin RNA enhances imatinib-induced cytotoxicity and promotes mitochondria-dependent intrinsic apoptosis. In contrast, knockdown of miR-30a by antagomir-30a increases the expression of Beclin 1 and ATG5, and inhibits imatinib-induced cytotoxicity. These findings indicate that dysregulation of miR-30a may interfere with the effectiveness of imatinib-mediated apoptosis by an autophagy-dependent pathway, thus representing a novel potential therapeutic target in CML.

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“…49 Another challenging point in CML is the eradication of leukemic stem cells (LSC) which is a prerequisite for the development of curative therapies. 50,51 There is growing evidence that TKIs fail to eliminate all primitive CML LSC in most patients. 51 A better understanding of the biology and target expression profiles, as well as of the relationship between BCR-ABL1 + LSC and their specific microenvironment in the bone marrow (niche), has paved the way for the development of new treatment approaches.…”

confidence: 99%

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

et al. 2014

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417 IntroductionSeveral new targets have recently been identified in neoplastic mast cells (MCs), and various targeted drugs have been examined for their effectiveness in malignant MC disorders. However, most drugs, including new KIT D816V-blocking agents, such as midostaurin (PKC412), 1 and various BCR-ABL1 inhibitors known to block KIT-activity, such as imatinib or dasatinib, 2 have failed to achieve long-lasting remissions in aggressive systemic mastocytosis (ASM). There is a similar problem in Ph + CML, where imatinib-resistant patients do not reach molecular remission even when secondor third-line BCR-ABL1 tyrosine kinase inhibitors (TKIs) are applied, particularly in patients exhibiting the BCR-ABL1 T315I mutant.3 During disease progression, additional signal transduction pathways become activated in neoplastic cells. Among these, AKT and STAT5 are critical downstream signaling molecules constitutively phosphorylated imatinibresistant chronic myeloid leukemia (CML) and KIT D816V + SM. 4,5 This has been demonstrated in vitro using KIT D816V + and BCR-ABL1 + imatinib-resistant cell lines, where inhibition of phosphorylation of these targets has shown their crucial role in cell proliferation. 6,7 It has also been reported that STAT5 and AKT remained activated in neoplastic myeloid cells, even after inhibition of BCR-ABL1 by TKIs. 8 Moreover, during disease progression, the levels of STAT5 mRNA and protein increase, and STAT5 production and activation is triggered not only by BCR-ABL1 or mutant KIT, but also by other pro-oncogenic pathways relevant to disease progression and resistance. 9 Taken together, these observations strongly suggest that STAT5 and AKT are key drivers in drug-resistant CML and SM, and thus represent potential therapeutic targets. Small molecules targeting STAT5 or AKT may indeed be effective in these malignancies, especially in TKIs-resistant patients. However, inhibitors available today, such as pimozide or BP-1-108 for STAT5, 10,11 or perifosine for AKT,12 are neither specific nor potent enough to be applicable in clinical practice. Therefore, it seems important to develop compounds that specifically and potently target STAT5 and AKT. Mast cells and mastocytosis KIT and cytokine signaling in normal mast cellsMCs originate from bone marrow (BM)-derived hematopoietic stem cells (HSCs) that enter the peripheral tissues via the bloodstream and undergo maturation under the Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy open-access paper. doi:10.3324/haematol.2013.098442 Manuscript received on October 8, 2013. Manuscript accepted on December 20, 2013 Chronic myeloid leukemia and systemic mastocytosis are myeloid neoplasms sharing a number of pathogenetic and clinical features. In both conditions, an aberrantly activated oncoprotein with tyrosine kinase activity, namely BCR-ABL1 in chronic myeloid leukemia, and mutant KIT, mostly KIT D816V, in systemic mastocytosis, is key to disease evolution. The appreciation of...

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Emerging stem cell concepts for imatinib‐resistant chronic myeloid leukaemia: implications for the biology, management, and therapy of the disease

Cited by 59 publications

References 198 publications

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

Glyoxalase-I is a novel target against Bcr-Abl+ leukemic cells acquiring stem-like characteristics in a hypoxic environment

Targeting microRNA-30a-mediated autophagy enhances imatinib activity against human chronic myeloid leukemia cells

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

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