Signal Transduction in the Chronic Leukemias: Implications for Targeted Therapies

Ahmed, Wesam; Etten, Richard A. Van

doi:10.1007/s11899-012-0150-1

Cited by 25 publications

(20 citation statements)

References 127 publications

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“…BCR-ABL1 activates a myriad of signaling pathways in hematopoietic cells, some of which are shared with those affecting normal HSCs. 42 Not all of these pathways appear to be required for leukemogenesis and it is likely that only a subset will contribute to the maintenance of the most primitive CML stem cells (Figure 1). How does one identify these signaling pathways, which could be mined for therapeutic targets?…”

Section: Targeting Signaling Pathways Implicated In CML Stem Cell Surmentioning

confidence: 99%

Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond

Ahmed

Etten

2013

Hematology

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In patients with chronic myeloid leukemia (CML) in chronic phase who have achieved complete molecular remission on imatinib therapy, clinical trials from France and Australia have demonstrated that the majority experience prompt molecular relapse of their leukemia upon discontinuation of the drug, showing that long-term monotherapy with tyrosine kinase inhibitors is not curative in the majority of patients with CML. This has focused attention on strategies to eradicate residual disease in CML that is presumed to arise from malignant Ph+ stem cells, which should result in permanent cure and long-term leukemia-free survival. Here, we review the evidence that targeting CML stem cells will be of clinical benefit and discuss pharmacological and immunological approaches to accomplish this goal. Where possible, we link preclinical studies of CML stem cell biology to emerging results from clinical trials of agents that may target these cells.

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Section: Targeting Signaling Pathways Implicated In CML Stem Cell Surmentioning

confidence: 99%

Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond

Ahmed

Etten

2013

Hematology

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“…Current research suggests that PI3K and mTOR are key points in the autophagy signaling pathway. 4,9 Among them, the pathway of type I PI3K and mTOR (especially mTOR complex 1, ie, mTORC1) inhibits the occurrence of autophagy. Type III PI3K promotes the occurrence of autophagy.…”

Section: Dovepressmentioning

confidence: 99%

“…[5][6][7] Therefore, people are still looking for new ways to treat CML. [8][9][10] The PI3K/Akt/ mTOR signaling pathway is located downstream of BCR-ABL and is an important signaling pathway in the pathogenesis of CML, 4,9 so this study attempts to treat CML by inhibiting the activity of this pathway. It is known that the PI3K/AKT/mTOR pathway is closely related to various cell functional activities such as cell proliferation, apoptosis and autophagy activity.…”

Section: Introductionmentioning

confidence: 99%

<p>Protective autophagy or autophagic death: effects of BEZ235 on chronic myelogenous leukemia</p>

Xin¹,

Xu²,

Zhu³

et al. 2019

CMAR

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Purpose: To investigate the effects of BEZ235 on chronic myeloid leukemia (CML) cells. Methods: MTS assay was used to detect the proliferation of CML cells. The proteins expression were detected by Western blot assay. The effects of BEZ235 on autophagy in CML cells were verified through transmission electron microscopy and evaluated by laser confocal microscopy. Annexin V-FITC/PI double staining flow cytometry was used to detect apoptosis. A xenograft model was established to observe the therapeutic effect of BEZ235 in vivo. Results: BEZ235 could inhibit the proliferation of CML cells; CQ and 3-MA could increase the proliferation inhibition and Z-VAD-FMK can reduce the proliferation inhibition of BEZ235 on CML cells (P<0.05). Results of TEM showed that the autophagosomes of CML cells treated with BEZ235 increased (P<0.05). The results by confocal microscopy showed that the autophagic activity of K562 cells increased with BEZ235 treatment. When BEZ235 combined with CQ, BEZ235-induced autophagic flow was blocked. FCM results showed that BEZ235 could induces apoptosis in CML cells. Z-VAD-FMK could decrease the apoptosis of CML cells induced by BEZ235. CQ increased the apoptosis of CML cells induced by BEZ235 (P<0.05). Western blot showed that BEZ235 inhibited the phosphorylation of AKT and S6K. BEZ235 alone could upregulate the expression of cleaved caspase-3 and LC3II. When combined with Z-VAD-FMK, the expression of cleaved caspase-3 was lower than that of BEZ235 alone. When combined with CQ, the expression of cleaved caspase-3 and LC3II were higher than those of BEZ235 alone (P<0.05). BEZ235 could inhibit the growth of xenografts of CML cell line. Conclusion: BEZ235 can inhibit the proliferation of CML cells, induce apoptosis, and enhance autophagy activity. It induces protective autophagy. The combination of CQ can enhance the apoptosis and proliferation inhibition of CML cells induced by BEZ235.

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“…12 In Ph + cell lines and mouse leukemia models, BCR-ABL1 is phosphorylated on Y177, which recruits the adaptor GRB2 and, thereby, the scaffolding adaptor GAB2. 14,15 Consequently, GAB2 is constitutively tyrosyl-phosphorylated and binds SHP2 and the p85 subunit of PI3K to activate the MEK/ERK and PI3K/AKT pathways, respectively. 16,17 Y177F mutation compromises myeloid transformation and leukemogenesis, [18][19][20] and GAB2 is required both for BCR-ABL1induced myeloid and lymphoid leukemogenesis.…”

Section: Introductionmentioning

confidence: 99%

SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasms

Sayad²,

Chan³

et al. 2017

Preprint

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BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph + ) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph + B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-offunction approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1 + B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1 + B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1 + , but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1 + pre-B cells, but is only required for the proliferation of BCR-ABL1 + cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1 + pre-B cells. RNAseq reveals distinct SHP2dependent transcriptional programs in BCR-ABL1 + and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.

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Signal Transduction in the Chronic Leukemias: Implications for Targeted Therapies

Cited by 25 publications

References 127 publications

Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond

Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond

<p>Protective autophagy or autophagic death: effects of BEZ235 on chronic myelogenous leukemia</p>

SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasms

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