Targeted therapy in T-cell malignancies: dysregulation of the cellular signaling pathways

Wl, Zhao

doi:10.1038/leu.2009.223

Cited by 95 publications

(75 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although the molecular pathogenesis of aggressive T-cell and NK cell malignancies remains unclear, ITK and RLK have been shown to be critical mediators of intracellular signaling that support the survival and growth of these malignancies (65)(66)(67). Our studies reveal that ITK-and RLK-based signaling in T-PLL can be blocked by PRN694, thereby starving these cells of an essential activation pathway.…”

Section: Discussionmentioning

confidence: 71%

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

Zhong

Dong

Strattan

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: ITK and RLK are unique to effector lymphocytes and critical for immune activation. Results: A novel selective covalent ITK/RLK inhibitor called PRN694 was discovered, which blocks T-cell and NK cell activation. Conclusion: PRN694 provides an effective tool to elucidate the roles of ITK and RLK in immune cell signaling. Significance: PRN694 could be an effective therapy for T-cell-or NK cell-driven autoimmune, inflammatory, and malignant diseases.

show abstract

Section: Discussionmentioning

confidence: 71%

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

Zhong

Dong

Strattan

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…12,13 PI3K/Akt activation is detected in about 85% of T-ALL patients and portends a poorer prognosis. 14,15 Moreover, when a constitutively active, myristoylated allele of Akt was introduced into murine hematopoietic cells, mice developed a T-cell lymphoma with high frequency (65%). 16 Of note, the evolution of T-cell lymphoma to T-ALL was dependent, among other molecular alterations, also on Akt hyperactivation.…”

Section: Introductionmentioning

confidence: 99%

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

et al. 2012

View full text Add to dashboard Cite

“…2 Therefore, novel and less toxic treatment strategies are needed that may target aberrantly activated signaling pathways influencing proliferation, survival and drug resistance of T-ALL cells. [3][4][5][6] About 85% of T-ALL patients display increased phosphatidylinositol 3-kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) activation at diagnosis, and this has a negative prognostic impact. [7][8][9] mTOR exists in two complexes that comprise distinct sets of proteinbinding partners.…”

Section: Introductionmentioning

confidence: 99%

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

et al. 2011

View full text Add to dashboard Cite

The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic subunit of two multi-protein complexes, referred to as mTORC1 and mTORC2. Signaling downstream of mTORC1 has a critical role in leukemic cell biology by controlling mRNA translation of genes involved in both cell survival and proliferation. mTORC1 activity can be down-modulated by upregulating the liver kinase B1/AMP-activated protein kinase (LKB1/AMPK) pathway. Here, we have explored the therapeutic potential of the anti-diabetic drug, metformin (an LKB1/AMPK activator), against both T-cell acute lymphoblastic leukemia (T-ALL) cell lines and primary samples from T-ALL patients displaying mTORC1 activation. Metformin affected T-ALL cell viability by inducing autophagy and apoptosis. However, it was much less toxic against proliferating CD4(+) T-lymphocytes from healthy donors. Western blot analysis demonstrated dephosphorylation of mTORC1 downstream targets. Unlike rapamycin, we found a marked inhibition of mRNA translation in T-ALL cells treated with metformin. Remarkably, metformin targeted the side population of T-ALL cell lines as well as a putative leukemia-initiating cell subpopulation (CD34(+)/CD7(-)/CD4(+)) in patient samples. In conclusion, metformin displayed a remarkable anti-leukemic activity, which emphasizes future development of LKB1/AMPK activators as clinical candidates for therapy in T-ALL. Leukemia (2012) 26, 91-100; doi:10.1038/leu.2011.269; published online 4 October 201

show abstract

Targeted therapy in T-cell malignancies: dysregulation of the cellular signaling pathways

Cited by 95 publications

References 116 publications

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

Contact Info

Product

Resources

About