EXPRESSION LEVELS OF JAK/STAT SIGNALING GENES IN NEWLY DIAGNOSED, DRUG SENSITIVE AND RESISTANT CHRONIC MYELOID LEUKEMIA PATIENTS
(Abstract release date: 05/21/15)
EHA Library. KIRAZ Y. 06/12/15; 102608; PB1736
Disclosure(s): ?zmir Institute of TechnologyMolecular Biology and Genetics
Yagmur KIRAZ
Contributions
Contributions
Abstract
Abstract: PB1736
Type: Publication Only
Background
Jak/STAT is a major intracellular signaling pathway that involved in immune response, cancer development (mostly leukemias) and hematopoiesis by stimulating cellular growth, proliferation and differentiation. This pathway relies on transmition of outside signals into the cells through cell membrane. The Jak/STAT mechanism composed of 2 main components including Janus kinase (Jak) and signal transducers and activators of transcription (STAT) proteins. Janus kinases, have four different types (Jak1, Jak2, Jak3 and Tyk2), found as an inactive form and associated with receptor protein on the cell membrane whereas there are seven types of STAT protein (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) that are located in cytoplasm and activated by Jak kinases. The system is started with conformational change and trans-activation of Jak proteins by a signal from a number of cytokines. This activation is followed by STAT phosphorylation at tyrosine residue in transactivation domain of STAT protein. Phosphorylated STAT proteins become dimerized by interacting phosphotyrosine of one STAT and SH2 domain of another STAT, as a result, they either affect different pathways and cause signaling cascades or move into the nucleus and directy activate their target genes involved in proliferation, differentiation, cell growth, cell death or survival. Abnormal activation of Jak/STAT signaling pathway proteins are found in many types of hematological malignancies including AML, MDS, B-cell lymphomas and CML.
Aims
Despite high efficiency of tyrosine kinase inhibitors, the success of therapy is limited to multidrug resistance phenomenon. Recent developments in drug resistance mechanism in CML showed that many molecular interactions and signaling pathways are involved in mediating TKI resistance in patients. Jak/STAT signaling pathway is one of these pathways that have significant roles in various cellular mechanisms including leukemia initiation and drug resistance.
Methods
This study including 14 newly diagnosed CML patients, 5 patients who are CML diagnosed and treated with imatinib, 1 patient who positively responded to imatinib, 1 patient who lost molecular response, 1 imatinib resistant patient and 1 patient who has both imatinib and nilotinib resistance. Mononuclear cells were isolated from bone marrow samples of the patients and total RNAs were isolated, mRNAs were converted into cDNAs and expression levels of JAK1-3, TYK2, STAT1-4, STAT5A-B and STAT6 genes were detected by Real-Time PCR.
Results
The results showed that expression levels of Jak3, STAT1-4 and STAT5A genes had higher in TKI resistant patients, compared to other patient groups. Expression levels of STAT5B, JAK1 and JAK2 genes were higher in newly diagnosed and positively responded patients than in resistant patients while expression levels of TYK2 was lower in imatinib-treated patients.
Summary
It was demonstrated for the first time that there is a relation between the clinical outcome of CML patients and expression levels of JAK-STAT genes that could make this signaling pathway a new target for more effective treatment of CML.
Keyword(s): Chronic myeloid leukemia, Imatinib resistance, Quantitative RT-PCR, STAT3
Type: Publication Only
Background
Jak/STAT is a major intracellular signaling pathway that involved in immune response, cancer development (mostly leukemias) and hematopoiesis by stimulating cellular growth, proliferation and differentiation. This pathway relies on transmition of outside signals into the cells through cell membrane. The Jak/STAT mechanism composed of 2 main components including Janus kinase (Jak) and signal transducers and activators of transcription (STAT) proteins. Janus kinases, have four different types (Jak1, Jak2, Jak3 and Tyk2), found as an inactive form and associated with receptor protein on the cell membrane whereas there are seven types of STAT protein (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) that are located in cytoplasm and activated by Jak kinases. The system is started with conformational change and trans-activation of Jak proteins by a signal from a number of cytokines. This activation is followed by STAT phosphorylation at tyrosine residue in transactivation domain of STAT protein. Phosphorylated STAT proteins become dimerized by interacting phosphotyrosine of one STAT and SH2 domain of another STAT, as a result, they either affect different pathways and cause signaling cascades or move into the nucleus and directy activate their target genes involved in proliferation, differentiation, cell growth, cell death or survival. Abnormal activation of Jak/STAT signaling pathway proteins are found in many types of hematological malignancies including AML, MDS, B-cell lymphomas and CML.
Aims
Despite high efficiency of tyrosine kinase inhibitors, the success of therapy is limited to multidrug resistance phenomenon. Recent developments in drug resistance mechanism in CML showed that many molecular interactions and signaling pathways are involved in mediating TKI resistance in patients. Jak/STAT signaling pathway is one of these pathways that have significant roles in various cellular mechanisms including leukemia initiation and drug resistance.
The aim of this study is to examine the relationship between expression levels of Jak/STAT genes and clinical outcome of chronic myeloid leukemia (CML) patients who are newly diagnosed; treated with imatinib, nilotinib or dasatinib; responded positively to TKIs; imatinib, nilotinib or dasatinib resistant; or lost of their molecular response.
Methods
This study including 14 newly diagnosed CML patients, 5 patients who are CML diagnosed and treated with imatinib, 1 patient who positively responded to imatinib, 1 patient who lost molecular response, 1 imatinib resistant patient and 1 patient who has both imatinib and nilotinib resistance. Mononuclear cells were isolated from bone marrow samples of the patients and total RNAs were isolated, mRNAs were converted into cDNAs and expression levels of JAK1-3, TYK2, STAT1-4, STAT5A-B and STAT6 genes were detected by Real-Time PCR.
Results
The results showed that expression levels of Jak3, STAT1-4 and STAT5A genes had higher in TKI resistant patients, compared to other patient groups. Expression levels of STAT5B, JAK1 and JAK2 genes were higher in newly diagnosed and positively responded patients than in resistant patients while expression levels of TYK2 was lower in imatinib-treated patients.
Summary
It was demonstrated for the first time that there is a relation between the clinical outcome of CML patients and expression levels of JAK-STAT genes that could make this signaling pathway a new target for more effective treatment of CML.
Keyword(s): Chronic myeloid leukemia, Imatinib resistance, Quantitative RT-PCR, STAT3
Abstract: PB1736
Type: Publication Only
Background
Jak/STAT is a major intracellular signaling pathway that involved in immune response, cancer development (mostly leukemias) and hematopoiesis by stimulating cellular growth, proliferation and differentiation. This pathway relies on transmition of outside signals into the cells through cell membrane. The Jak/STAT mechanism composed of 2 main components including Janus kinase (Jak) and signal transducers and activators of transcription (STAT) proteins. Janus kinases, have four different types (Jak1, Jak2, Jak3 and Tyk2), found as an inactive form and associated with receptor protein on the cell membrane whereas there are seven types of STAT protein (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) that are located in cytoplasm and activated by Jak kinases. The system is started with conformational change and trans-activation of Jak proteins by a signal from a number of cytokines. This activation is followed by STAT phosphorylation at tyrosine residue in transactivation domain of STAT protein. Phosphorylated STAT proteins become dimerized by interacting phosphotyrosine of one STAT and SH2 domain of another STAT, as a result, they either affect different pathways and cause signaling cascades or move into the nucleus and directy activate their target genes involved in proliferation, differentiation, cell growth, cell death or survival. Abnormal activation of Jak/STAT signaling pathway proteins are found in many types of hematological malignancies including AML, MDS, B-cell lymphomas and CML.
Aims
Despite high efficiency of tyrosine kinase inhibitors, the success of therapy is limited to multidrug resistance phenomenon. Recent developments in drug resistance mechanism in CML showed that many molecular interactions and signaling pathways are involved in mediating TKI resistance in patients. Jak/STAT signaling pathway is one of these pathways that have significant roles in various cellular mechanisms including leukemia initiation and drug resistance.
Methods
This study including 14 newly diagnosed CML patients, 5 patients who are CML diagnosed and treated with imatinib, 1 patient who positively responded to imatinib, 1 patient who lost molecular response, 1 imatinib resistant patient and 1 patient who has both imatinib and nilotinib resistance. Mononuclear cells were isolated from bone marrow samples of the patients and total RNAs were isolated, mRNAs were converted into cDNAs and expression levels of JAK1-3, TYK2, STAT1-4, STAT5A-B and STAT6 genes were detected by Real-Time PCR.
Results
The results showed that expression levels of Jak3, STAT1-4 and STAT5A genes had higher in TKI resistant patients, compared to other patient groups. Expression levels of STAT5B, JAK1 and JAK2 genes were higher in newly diagnosed and positively responded patients than in resistant patients while expression levels of TYK2 was lower in imatinib-treated patients.
Summary
It was demonstrated for the first time that there is a relation between the clinical outcome of CML patients and expression levels of JAK-STAT genes that could make this signaling pathway a new target for more effective treatment of CML.
Keyword(s): Chronic myeloid leukemia, Imatinib resistance, Quantitative RT-PCR, STAT3
Type: Publication Only
Background
Jak/STAT is a major intracellular signaling pathway that involved in immune response, cancer development (mostly leukemias) and hematopoiesis by stimulating cellular growth, proliferation and differentiation. This pathway relies on transmition of outside signals into the cells through cell membrane. The Jak/STAT mechanism composed of 2 main components including Janus kinase (Jak) and signal transducers and activators of transcription (STAT) proteins. Janus kinases, have four different types (Jak1, Jak2, Jak3 and Tyk2), found as an inactive form and associated with receptor protein on the cell membrane whereas there are seven types of STAT protein (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) that are located in cytoplasm and activated by Jak kinases. The system is started with conformational change and trans-activation of Jak proteins by a signal from a number of cytokines. This activation is followed by STAT phosphorylation at tyrosine residue in transactivation domain of STAT protein. Phosphorylated STAT proteins become dimerized by interacting phosphotyrosine of one STAT and SH2 domain of another STAT, as a result, they either affect different pathways and cause signaling cascades or move into the nucleus and directy activate their target genes involved in proliferation, differentiation, cell growth, cell death or survival. Abnormal activation of Jak/STAT signaling pathway proteins are found in many types of hematological malignancies including AML, MDS, B-cell lymphomas and CML.
Aims
Despite high efficiency of tyrosine kinase inhibitors, the success of therapy is limited to multidrug resistance phenomenon. Recent developments in drug resistance mechanism in CML showed that many molecular interactions and signaling pathways are involved in mediating TKI resistance in patients. Jak/STAT signaling pathway is one of these pathways that have significant roles in various cellular mechanisms including leukemia initiation and drug resistance.
The aim of this study is to examine the relationship between expression levels of Jak/STAT genes and clinical outcome of chronic myeloid leukemia (CML) patients who are newly diagnosed; treated with imatinib, nilotinib or dasatinib; responded positively to TKIs; imatinib, nilotinib or dasatinib resistant; or lost of their molecular response.
Methods
This study including 14 newly diagnosed CML patients, 5 patients who are CML diagnosed and treated with imatinib, 1 patient who positively responded to imatinib, 1 patient who lost molecular response, 1 imatinib resistant patient and 1 patient who has both imatinib and nilotinib resistance. Mononuclear cells were isolated from bone marrow samples of the patients and total RNAs were isolated, mRNAs were converted into cDNAs and expression levels of JAK1-3, TYK2, STAT1-4, STAT5A-B and STAT6 genes were detected by Real-Time PCR.
Results
The results showed that expression levels of Jak3, STAT1-4 and STAT5A genes had higher in TKI resistant patients, compared to other patient groups. Expression levels of STAT5B, JAK1 and JAK2 genes were higher in newly diagnosed and positively responded patients than in resistant patients while expression levels of TYK2 was lower in imatinib-treated patients.
Summary
It was demonstrated for the first time that there is a relation between the clinical outcome of CML patients and expression levels of JAK-STAT genes that could make this signaling pathway a new target for more effective treatment of CML.
Keyword(s): Chronic myeloid leukemia, Imatinib resistance, Quantitative RT-PCR, STAT3
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