BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571

Donato, Nicholas J.; Wu, Ji Yuan; Stapley, Jonathan; Gallick, Gary E.; Lin, Hui-Kuan; Arlinghaus, Ralph B.; Talpaz, Moshe

doi:10.1182/blood.v101.2.690

Cited by 603 publications

(522 citation statements)

References 42 publications

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“…The role of the Src kinases in the leukaemogenic potential of Tel-Abl remains therefore questionable. However, the situation may be different in the development of CML in human because Bcr-Abl-expressing cell lines or CD34 þ from CML patients resistant or not to imatinib mesylate treatment are sensitive to Src inhibitors or to downregulation of Src expression (Donato et al, 2003;Dai et al, 2004). Our results support the use of Src inhibitors in the treatment of leukaemia associated with oncogenic activation of c-Abl.…”

Section: Discussionsupporting

confidence: 63%

“…A number of human primary tumours and tumour-derived cell lines including leukaemias possess elevated Src kinase activities (Rosen et al, 1986;Ottenhoff-Kalff et al, 1992;Talamonti et al, 1993;Mao et al, 1997;Donato et al, 2003). For instance, Lyn and Hck have been implicated in the oncogenic activity of Bcr-Abl in haematopoietic cells (Danhauser-Riedl et al, 1996;Hu, Nature genetics, 2004) and with the use of dominant-negative src mutants or pharmacological inhibitors have confirmed that these two kinases contribute to the Bcr-Abl-induced Tel-Abl induces oncogenic signalling via Hck C Pecquet et al Bcr-Abl-transformed haematopoietic cells.…”

Section: Discussionmentioning

confidence: 99%

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The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

et al. 2006

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

et al. 2006

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“…However, other mechanisms have also been implicated including the duplication and amplification of the BCR-ABL (Weisberg and Griffin, 2000;le Coutre et al, 2000). Imatinib export via the p-glycoprotein efflux pump (Mahon et al, 2000), reduced expression of the organic cation transporter OCT1 (Crossman et al, 2005;Wang et al, 2008), binding of imatinib to the plasma by a1-acid glycoprotein (Gambacorti-Passerini et al, 2003a) and the activation of alternative signaling cascades leading to BCR-ABL-independent growth (Donato et al, 2003;Ptasznik et al, 2004). With regard to STAP-2 expression, one gene expression database on CML patient samples reported that STAP-2 was expressed by CD34 þ cells (D Bruennert, 2009).…”

Section: Discussionmentioning

confidence: 99%

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

et al. 2012

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In chronic myeloid leukemia (CML), the BCR-ABL fusion oncoprotein activates multiple pathways involved in cell survival, growth promotion and disease progression. In this report, we show that the signal transducing adaptor protein-2 (STAP-2) is involved in BCR-ABL activity. We demonstrate that STAP-2 bound to BCR-ABL, and BCR and ABL proteins, depending on the STAP-2 Src homology 2-like domain. BCR-ABL phosphorylates STAP-2 Tyr250 and the phosphorylated STAP-2 in turn up-regulated BCR-ABL phosphorylation, leading to enhanced activation of downstream signaling molecules including ERK, STAT5, BCL-xL and BCL-2. In addition, STAP-2 interacts with BCR-ABL to alter chemokine receptor expression leading to downregulation of CXCR4 and upregulation of CCR7. The interaction between STAP-2 and BCR-ABL plays a crucial role in conferring a growth advantage and resistance to imatinib, a BCR-ABL inhibitor, as well as tumor progression. Notably, mice injected with BCR-ABL/STAP-2-expressing Ba/F3 cells developed lymph node enlargement and hepatosplenomegaly. Moreover, suppression of STAP-2 in K562 CML cells resulted in no tumor formation in mice. Our results demonstrate a critical contribution of STAP-2 in BCR-ABL activity, and suggest that STAP-2 might be an important candidate for drug development for patients with CML. Further, the expression of STAP-2 provides useful information for estimating the characteristics of individual CML clones

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“…In blast crisis, increased expression of the BCR/ ABL oncoprotein accounts for the block of differentiation, inactivation of factors with tumour suppressor activity and decreased genomic stability of the Ph 1 blasts Skorski, 2002;Trotta et al, 2003;Calabretta and Perrotti, 2004;Neviani et al, 2005). Thus, dependence on BCR/ABL expression is not only a characteristic of CML-CP but also of CML-BC; however, BCR/ABL-independent mechanisms also seem to contribute to disease progression and imatinib resistance in some CML cases (Donato et al, 2003;Dai et al, 2004).…”

Section: CML Bcr/abl and Imatinibmentioning

confidence: 99%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571

Cited by 603 publications

References 42 publications

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

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