Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy

Mustjoki, Satu; Ekblom, Marja; Arstila, T. Petteri; Dybedal, Ingunn; Epling-Burnette, Pearlie K.; Guilhot, Joëlle; Hjorth‐Hansen, Henrik; Höglund, Martin; Kovanen, Panu E.; Laurinolli, Tuisku; Liesveld, Jane L.; Paquette, Ronald; Pinilla‐Ibarz, Javier; Rauhala, Auvo; Shah, Neil P.; Simonsson, Bengt; Sinisalo, Marjatta; Steegmann, Juan Luis; Stenke, Leif; Porkka, Kimmo

doi:10.1038/leu.2009.46

Cited by 292 publications

(326 citation statements)

References 20 publications

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“…21 In addition, patients with or without pleural effusion showed similar progression-free and overall survival, and cytogenetic response rates were higher in patients with a pleural effusion. 21 Other studies have presented that patients with lymphocytosis during dasatinib treatment achieved favorable response rate 22,23 and in parallel with this case report result.…”

Section: Discussionsupporting

confidence: 76%

Effective Molecular Monitoring and the Proper Management of Pleural Effusion During the First-Line Dasatinib Administration in CML

Aksu¹,

Bektas²,

Uz³

et al. 2012

UHOD

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Dasatinib is considered an effective treatment agent in imatinib-resistant and newly diagnosed chronic phase CML patients. Patients receiving dasatinib 100 mg once daily regime suffered significantly fewer thrombocytopenia and pleural effusion events than those receving 70 mg twice daily. Effective molecular monitoring and the proper management of pleural effusion during the first-line dasatinib administration in CML are essential. Pleural effusion may develop any time of the treatment and is easily managed by treatment interruption, dose reduction and supportive therapy. In this article, we intended to assess the rational of managing CML and pleural effusion that successfully managed with dose reduction and supportive care.Keywords: Dasatinib, First-line therapy, Chronic myeloid leukemia, Pleural effusion ÖZET Kronik Myelositier Lösemide Birinci Basamak Tedavi S›ras›nda Oluflan Plevral Efüzyonun Yönetimi ve Etkin Moleküler ‹zlemDasatinib, imatinibe dirençli ve yeni tan› alm›fl kronik faz KML hastalar›nda etkin bir tedavi ajan› olarak düflünülmektedir. Günde 100 mg tek doz dasatinib tedavisi alan hastalar›n günde 70 mg iki kez tedavisi alanlara göre anlaml› oranda daha düflük trombositopeni ve plevral efüzyon gelifltirdikleri gösterilmifltir. KML'de moleküler monitörizasyonun dikkatli yap›lmas› ve ilk s›ra dasatinib verilen hastalarda plevral effüzyonun yönetilmesi büyük önem tafl›maktad›r. Plevral efüzyonun dasatinib tedavisinin herhangi bir zaman›nda ortaya ç›kabilmekte ve doza ara verme, doz azaltma, ve destek tedaviler ile kolayl›kla yönetilebilmektedir. Bu çal›flmada, KML ve plevral efüzyonun baflar›yla yönetimine iliflkin moleküler yöntemler araflt›r›lacakt›r.Anahtar Kelimeler: Dasatinib, ‹lk-basamak tedavi, Kronik miyeloid lösemi, Plevral efüzyon ULUSLARARASı HEMATOLOJI-ONKOLOJI DERGISI ARTICLE

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Section: Discussionsupporting

confidence: 76%

Effective Molecular Monitoring and the Proper Management of Pleural Effusion During the First-Line Dasatinib Administration in CML

Aksu¹,

Bektas²,

Uz³

et al. 2012

UHOD

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“…Recent evidence that dasatinib, a broad-spectrum tyrosine kinase inhibitor currently used for treatment of Philadelphia chromosomepositive leukemias, induces a significant expansion of LGL cells highlights the relevance of signaling pathways in the pathogenesis of LGL disorders. 49,50 In order to gain insight into the characteristics of LGL proliferations, further knowledge of the development pathways of normal LGL cell is essential. Investigation of disease pathogenesis will lead to the identification of molecular targets and the discovery of more efficacious and less toxic treatments.…”

mentioning

confidence: 99%

Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

Zambello¹,

Semenzato²

2009

Haematologica

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F e r r a t a S t o r t i F o u n d a t i o nhaplotype with a higher frequency than the normal population, as occurs in patients with rheumatoid arthritis. In recent years progress has been made in understanding the mechanisms sustaining T-LGL leukemia and CLPD-NK. It is now becoming evident that the phenotype of T-cell LGL leukemia is consistent with that of fully differentiated cytotoxic T lymphocytes. The hallmark of T-LGL leukemia lymphocytes is the failure to undergo activation-induced cell death (AICD), this event being consequent to a critical impairment of apoptotic pathways. T-LGL leukemia is characterized by an abnormal clonal expansion of antigen-primed mature cytotoxic T-lymphocytes (CTL) which successfully escape AICD and remain competent in the long-term. 10 Clearance of potentially harmful antigen-stimulated effector cytotoxic T-cells after a successful immune response occurs physiologically by triggering Fas-mediated apoptosis through induction of a death-inducing signaling complex (DISC). This process, which is crucial to T-cell homeostasis, requires fine tuning between proliferation, survival, and apoptosis. Like normal activated CTL, leukemic T-LGL cells exhibit activation of multiple survival signaling pathways. 6 However, unlike normal activated CTL, leukemic T-LGL cells are not sensitive to Fas-induced apoptosis, 20 a process that is essential for AICD. 21 Fas resistance can occur in cells with overexpression of the DISC inhibitory protein c-FLIP. This latter is constitutively expressed in leukemic LGL and prevents DISC formation and Fas-mediated apoptosis. 22 Several genes are likely to be involved in the above mentioned processes and gene expression profiling has revealed that leukemic LGL are characterized by the expression of genes affecting apoptosis, regulation of TCR signaling and immune response. 23 This supports the view that an uncoupling of activation and apoptotic pathways is responsible for the failure of AICD. In fact, genes that are up-regulated in leukemic LGL have antiapoptotic functions whereas those that are down-regulated are pro-apoptotic. Pathway-based microarray analysis also indicated that the balance of pro-apoptotic (ceramide and its analogs) and anti-apoptotic (sphingosine-1-phosphate, S1P) sphingolipid-mediated signaling is deregulated in leukemic LGL in favor of S1P. 23 Of great interest is the model suggesting that the persistence of interleukin-15 and platelet-derived growth factor is sufficient to reproduce all known deregulations in leukemic T-LGL. 10 Interleukin-15 alters expression of Bcl-2 family members, i.e. Bcl-2, Bcl-XL, Bim, Noxa, and Mcl-1. Genes belonging to the BCL-2 family, such as the BCL-2 related X gene (BAX) are down-regulated, while the myeloid cell factor (MCL-1) is up-regulated. In primary leukemic LGL, Bid (which is down-regulated by interleukin-15) levels are low but are reversed following bortezomib treatment, with subsequent increases in LGL apoptosis. These data provide a novel molecular mechanism for interleukin-15 control of Bid whi...

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“…29 Importantly, despite the immunosuppressive activities reported for both drugs in vitro, functional T-cell responses were reported to develop in CML patients on imatinib, [32][33][34] and clonal lymphoproliferation was observed in some patients on dasatinib and was associated with favorable clinical responses. [35][36][37][38] Thus, further in vivo studies are needed to discern the effects of TKIs on immune effector cells.…”

Section: Introductionmentioning

confidence: 99%

NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR–ABL-positive mice

et al. 2011

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Although BCR-ABL þ stem cells in chronic myeloid leukemia (CML) resist elimination by targeted pharmacotherapy in most patients, immunological graft-versus-leukemia effects can cure the disease. Besides cytotoxic T cells, natural killer (NK) cells may have a role in immune control of CML. Here, we explored the functionality of NK cells in CML patients and in a transgenic inducible BCR-ABL mouse model. Compared with controls, NK-cell proportions among lymphocytes were decreased at diagnosis of CML and did not recover during imatinib-induced remission for 10-34 months. Functional experiments revealed limited in vitro expansion of NK cells from CML patients and a reduced degranulation response to K562 target cells both at diagnosis and during imatinib therapy. Consistent with the results in human CML, relative numbers of NK1.1 þ NK cells were reduced following induction of BCR-ABL expression in mice, and the defects persisted after BCR-ABL reversion. Moreover, target-induced degranulation by expanded BCR-ABL þ NK cells was compromised. We conclude that CML is associated with quantitative and functional defects within the NK-cell compartment, which is reproduced by induced BCR-ABL expression in mice. Further work will aim at identifying the mechanisms of NK-cell deficiency in CML and at developing strategies to exploit NK cells for immunotherapy.

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Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy

Cited by 292 publications

References 20 publications

Effective Molecular Monitoring and the Proper Management of Pleural Effusion During the First-Line Dasatinib Administration in CML

Effective Molecular Monitoring and the Proper Management of Pleural Effusion During the First-Line Dasatinib Administration in CML

Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches

NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR–ABL-positive mice

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