Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

Abdelrasoul, Hend; Vadakumchery, Anila; Werner, Markus; Lenk, Lennart; Khadour, Ahmad; Young, Marc; Ayoubi, Omar El; Vogiatzi, Fotini; Krämer, M.; Schmid, Vera; Chen, Zhengshan; Yousafzai, Yasar Mehmood; Cario, Gunnar; Schrappe, Martin; Müschen, Markus; Halsey, Christina; Mulaw, Medhanie A.; Schewe, Denis; Hobeika, Elias; Alsadeq, Ameera; Jumaa, Hassan

doi:10.1038/s41467-020-16927-w

Cited by 15 publications

(18 citation statements)

References 63 publications

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“…Calcium ions (Ca 2+ ) are important intracellular messengers since they exert regulatory effects on cytosolic enzymes and proteins and are often induced after CXCR4 activation 39 . Thus, in the next set of experiments, the effect of EPI-X4, its analogs and AMD3100 on CXCL12-induced intracellular Ca 2+ mobilization was analyzed in BCR-ABL transformed bone marrow cells via flow cytometry 40 . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

Harms

Habib

Nemska

et al. 2021

Acta Pharmaceutica Sinica B

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Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases. A natural fragment of serum albumin, named EPI-X4, has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases. To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4. Subsequent rational drug design allowed to increase the anti-CXCR4 activity of EPI-X4. The EPI-X4 derivative JM#21 bound CXCR4 and suppressed CXCR4-tropic HIV-1 infection more efficiently than the clinically approved small molecule CXCR4 antagonist AMD3100. EPI-X4 JM#21 did not exert toxic effects in zebrafish embryos and suppressed allergen-induced infiltration of eosinophils and other immune cells into the airways of animals in an asthma mouse model. Moreover, topical administration of the optimized EPI-X4 derivative efficiently prevented inflammation of the skin in a mouse model of atopic dermatitis. Thus, rationally designed EPI-X4 JM#21 is a novel potent antagonist of CXCR4 and the first CXCR4 inhibitor with therapeutic efficacy in atopic dermatitis. Further clinical development of this new class of CXCR4 antagonists for the therapy of atopic dermatitis, asthma and other CXCR4-associated diseases is highly warranted.

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Section: Resultsmentioning

confidence: 99%

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

Harms

Habib

Nemska

et al. 2021

Acta Pharmaceutica Sinica B

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“…Alternatively, TKI-targeting Bcr-Abl1 in patients with CML or ALL have brought responsive patients a close-to-normal life span [ 1 ]. The Bcr-Abl1 fusion protein ultimately activates myeloid cell growth and proliferation that signals through multiple oncogenic pathways [ 11 , 51 , 52 ].…”

Section: Pathogenic Function Of Bcr-abl1 Kinase Fusion Proteinsmentioning

confidence: 99%

Ponatinib and other CML Tyrosine Kinase Inhibitors in Thrombosis

Zeng

2020

IJMS

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Abl1 kinase has important biological roles. The Bcr-Abl1 fusion protein creates undesired kinase activity and is pathogenic in 95% of chronic myeloid leukemia (CML) and 30% of acute lymphoblastic leukemia (ALL) patients. Targeted therapies to these diseases are tyrosine kinase inhibitors. The extent of a tyrosine kinase inhibitor’s targets determines the degree of biologic effects of the agent that may influence the well-being of the patient. This fact is especially true with tyrosine kinase inhibitor effects on the cardiovascular system. Thirty-one percent of ponatinib-treated patients, the tyrosine kinase inhibitor with the broadest inhibitory spectrum, have thrombosis associated with its use. Recent experimental investigations have indicated the mechanisms of ponatinib-associated thrombosis. Further, an antidote to ponatinib is in development by re-purposing an FDA-approved medication.

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“…SOCS2 mRNA levels were elevated in high-risk AML and ALL harboring MLL and BCR-ABL chromosomal rearrangements. Upregulation of SOCS2 correlated with the enrichment in hematopoietic and leukemic stemness genes [69,70]. SOCS2 overexpression was also reported in AML cell lines and primary samples carrying FLT3-ITD mutations [105].…”

Section: Cis and Socs2mentioning

confidence: 70%

The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia

Keewan

Matławska-Wasowska

2021

Cancers

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Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.

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Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia

Cited by 15 publications

References 63 publications

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation

Ponatinib and other CML Tyrosine Kinase Inhibitors in Thrombosis

The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia

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