Upregulation of the TGFβ signalling pathway by Bcr‐Abl: Implications for haemopoietic cell growth and chronic myeloid leukaemia

Møller, Gigi M. O.; Frost, Victoria; Melo, Junia V.; Chantry, Andrew

doi:10.1016/j.febslet.2007.02.048

Cited by 32 publications

(25 citation statements)

References 27 publications

(38 reference statements)

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“…Furthermore, although imatinib treatment alone of LICs co-cultured with OP-9 cells reduced the colony-forming capacity of Foxo3a 1/1 CML LICs, the addition of TGF-b inhibitor significantly enhanced the inhibitory effect of imatinib on LIC colony-forming ability (Fig. 3f and Supplementary Figs 17b, c and 18a), consistent with a report in which TGF-b inhibition enhanced imatinib-induced cell death 24 . Although Foxo3a deficiency alone did not affect LIC colony-forming ability (Fig.…”

supporting

confidence: 79%

TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

Naka

Hoshii

Muraguchi

et al. 2010

Nature

538

508

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Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase 1 . It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells [2][3][4] . Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemiainitiating cells (LICs) that drive the recurrence of CML [5][6][7][8] . Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a 1/1 and Foxo3a 2/2 mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-b is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-b inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-b inhibitor impaired their colonyforming ability in vitro. Our results demonstrate a critical role for the TGF-b-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.Although tyrosine kinase inhibitor (TKI) therapy of CML patients efficiently induces the death of leukaemia cells [5][6][7][8] , LICs in these patients can survive this therapy. To understand the molecular mechanisms maintaining CML LICs, we characterized LICs in vivo using a mouse model for CML-like myeloproliferative disease (MPD) 9 . Consistent with previous reports 10-13 , we found that a rare c-Kit 1 Lineage 2 (Lin 2 )Sca-1 1 (KLS 1 ) population of CML cells (that is, bearing markers of normal haematopoietic stem cells (HSCs)) induced efficient CML development in recipient mice (Supplementary Fig. 1). In contrast, neither c-Kit 1 Lin 2 Sca-1 2 (KLS 2 ) cells (which correspond to normal progenitors), nor other CML cell populations expressing differentiation markers, induced CML.We and others have shown that Foxo transcription factors, which are important downstream targets of PI3K-Akt signalling, are essential for the maintenance of self-renewal capacity in normal HSCs [14][15][16] . When a growth factor binds to the appropriate receptor, Akt is activated and phosphorylates Foxo proteins, resulting in their nuclear export and subsequent degradation in the cytoplasm. In the absence of growth factor stimulation, Foxo proteins are retained in an active state in the nucleus and induce their transcriptional targets. In CML cell lines, BCR-ABL is thought to activate PI3K-Akt signalling that leads to nuclear export of Foxo factors and suppression of their transcriptional activity...

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supporting

confidence: 79%

TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

Naka

Hoshii

Muraguchi

et al. 2010

Nature

538

508

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“…The higher c-FLIP expression observed in IM-resistant patients may be linked to the elevated TGF-β 1 in BCR-ABL-positive cells [29,30]. The complete eradication of CML is hindered by a small pocket of hematopoietic stem cells, which are resistant to IM, in part because they are not cycling [29].…”

Section: Discussionmentioning

confidence: 99%

Apoptosis-Related Gene Expression Profile in Chronic Myeloid Leukemia Patients after Imatinib Mesylate and Dasatinib Therapy

et al. 2015

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Background/Aims: We investigated the effects of tyrosine kinase inhibitors (TKIs) on the expression of apoptosis-related genes (BCL-2 and death receptor family members) in chronic myeloid leukemia (CML) patients. Methods: Peripheral blood mononuclear cells from 32 healthy subjects and 26 CML patients were evaluated before and after treatment with imatinib mesylate (IM) and dasatinib (DAS) by quantitative PCR. Results: Anti-apoptotic genes (c-FLIP and MCL-1) were overexpressed and the pro-apoptotic BIK was reduced in CML patients. Expression of BMF, A1, c-FLIP, MCL-1, CIAP-2 and CIAP-1 was modulated by DAS. In IM-resistant patients, expression of A1, c-FLIP, CIAP-1 and MCL-1 was upregulated, and BCL-2, CIAP-2, BAK, BAX, BIK and FASL expression was downregulated. Conclusion: Taken together, our results point out that, in CML, DAS interferes with the apoptotic machinery regulation. In addition, the data suggest that apoptosis-related gene expression profiles are associated with primary resistance to IM.

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“…For example, treatment of human CML stem cells with the TGF-β inhibitor, LY364947 limited their clonogenic activity in vitro (243). Similarly, TGF-β inhibition using SB431542 observed a reduction in the growth of CD34 + cells isolated from human chronicphase CML samples, and enhancing cell death in combination with imatinib in nonproliferating CML cells (234). Most recently, upregulation of Smo was associated with reduced expression of microRNA-326 in leukemic CD34 + progenitor cells collected from human patients with CML at diagnosis compared to healthy controls (16).…”

Section: Antioxidants and Redox Signalingmentioning

confidence: 95%

The Implication of Cancer Progenitor Cells and the Role of Epigenetics in the Development of Novel Therapeutic Strategies for Chronic Myeloid Leukemia

Tortorella

Hung

Karagiannis

2015

Antioxidants & Redox Signaling

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Upregulation of the TGFβ signalling pathway by Bcr‐Abl: Implications for haemopoietic cell growth and chronic myeloid leukaemia

Cited by 32 publications

References 27 publications

TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

TGF-β–FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia

Apoptosis-Related Gene Expression Profile in Chronic Myeloid Leukemia Patients after Imatinib Mesylate and Dasatinib Therapy

The Implication of Cancer Progenitor Cells and the Role of Epigenetics in the Development of Novel Therapeutic Strategies for Chronic Myeloid Leukemia

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