INCREASED PLASMA NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPT) IS ASSOCIATED WITH A HYPERPROLIFERATIVE PHENOTYPE AND RESTRAINS DISEASE PROGRESSION IN MPN-ASSOCIATED MYELOFIBROSIS
(Abstract release date: 05/19/16)
EHA Library. Rosti V. 06/09/16; 132884; E1335
Dr. Vittorio Rosti
Contributions
Contributions
Abstract
Abstract: E1335
Type: Eposter Presentation
Background
Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a clonal, neoplastic disorder of the hematopoietic stem cells, in which inflammation and immune dysregulation play an important role. Somatic mutations of JAK2 (JAK2V617F), CALR or MPL genes ar pathogenetically linked to the disorder. JAK-STAT pathway activation is the main mechanism of myeloproliferation; however, available evidence indicates that inflammatory/immune mechanisms play an important role in the phenotype of MPN-associated myelofibrosis by increased production of inflammatory cytokines and reduced number of regulatory T-cells. Nicotinamide phosphoribosyltransferase (NAMPT), intracellularly, is an enzyme that converts nicotinamide into nicotinamide mononucleotide, precursor of nicotinamide adenine dinucleotide (NAD+), which is essential for cellular metabolism, energy production, DNA repair, and survival. NAMPT exists also as an extracellular protein defined in literature as Pre-B cell colony-enhancing factor (PBEF) or as an adipokine called visfatin. Different type of cells are able to release this protein, but its role as a cytokine is still unknown. Emerging data implicate eNAMPT in the pathogenesis of a number of different human diseases that share an inflammatory basis, such as rheumatoid arthritis, type 2 diabetes, acute life-threatening processes such as acute lung injury, sepsis, and tumorigenesis. In the tumour microenvironment, e-NAMPT induces monocyte polarization to M2 macrophages secreting tumor-promoting cytokines and inhibiting T-cell responses rendering this pleiotropic molecule a novel player in tumor/host cross-talk. The function of NAMPT in MPN-associated myelofibrosis biology is completely unknown
Aims
Here we examined plasma levels of eNAMPT in patients with MPN-associated myelofibrosis and their effects on disease phenotype and outcomes. We also studied the concordance of eNAMPT levels with the marker of general inflammation high-sensitivity C-reactive protein (hs-CRP).
Methods
A total of 333 MPN-associated myelofibrosis patients (187 males and 146 females) and 31 age- and gender-matched normal-weight controls were enrolled in the study. The control group was selected among the general population excluding individuals with a body mass index greater than 25. At study entrance, all participants gave their informed consent, and study protocol was approved by the Ethics Committee of our Hospital before implementation. Since there is no accepted definition of disease severity, we evaluated a 'severity score' by indexing leukocytosis, thrombocytosis, and splenomegaly (myeloproliferation index), and anemia, leukopenia, and thrombocytopenia (myelodepletion index) Levels of eNAMPT and hs-CRP were simultaneously assayed in 209 MPN-associated myelofibrosis patients. Twenty-four polycythemia vera or essential thrombocythemia patients were used as controls. eNAMPT levels were measured using a commercial immunoassay kit (BioPlex, BioRad Hercules, CA, USA) according to manufacturer instructions. All samples were assayed in duplicate.
Results
In the 333 MPN-associated myelofibrosis patients enrolled in the study main body, risk stratification according to the IPSS/DIPSS prognostic scoring system showed a predominance of low and intermediate I risk classes (74% of the patients). The severity score of the disease based on spleen size and hematological parameters measured at the time of eNAMPT analysis ranged from 0 to 6 with a median value of 3. The “myeloproliferation index” (range 0 to 4) had a median value of 3 and was equal to or lower than 1 in 39 patients (46.4%), while the “myelodepletion index” (range 0 to 4) had a median value of 2 and was equal to or lower than 1 in 34 patients (40.5%). eNAMPT was over expressed in MPN-associated myelofibrosis (n=333, median 1,487 ng/L, range 81-96,031) compared to healthy subjects (n=31, median 268 ng/L, range 81-4,981; P=0.001). There was no difference in the median eNAMPT level between patients with PMF and post-PV or post-ET myelofibrosis. eNAMPT expression was correlated with higher white blood cell count (R=0.13;P=0.029), higher hemoglobin (R=0.20;P<0.001) and higher platelet count (R=0.25;P=<0.001), suggesting that eNAMPT is an indispensable permissive agent for myeloproliferation of MPN-associated myelofibrosis. In 209 patients with MPN-associated myelofibrosis we simultaneously assayed eNAMPT and hs-CRP. Patients with MPN-associated myelofibrosis had higher levels of hs-CRP than healthy controls (median, 0.15 ng/µl, range, 0.02 to 11.4). However, the individual values of eNAMPT were not correlated with those of hs-CRP level, suggesting that eNAMPT in MPN-associated myelofibrosis does not behave as a canonical inflammatory cytokine. In addition, higher levels of eNAMPT predicted longer time to blast transformation, and protected against progression towards thrombocytopenia and large splenomegaly.
Conclusion
In conclusion, in MPN-associated myelofibrosis high levels of eNAMPT mark the myeloproliferative potential and, at variance with a high number of cancers, are protective against disease progression.
Session topic: E-poster
Keyword(s): Inflammation, Myelofibrosis
Type: Eposter Presentation
Background
Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a clonal, neoplastic disorder of the hematopoietic stem cells, in which inflammation and immune dysregulation play an important role. Somatic mutations of JAK2 (JAK2V617F), CALR or MPL genes ar pathogenetically linked to the disorder. JAK-STAT pathway activation is the main mechanism of myeloproliferation; however, available evidence indicates that inflammatory/immune mechanisms play an important role in the phenotype of MPN-associated myelofibrosis by increased production of inflammatory cytokines and reduced number of regulatory T-cells. Nicotinamide phosphoribosyltransferase (NAMPT), intracellularly, is an enzyme that converts nicotinamide into nicotinamide mononucleotide, precursor of nicotinamide adenine dinucleotide (NAD+), which is essential for cellular metabolism, energy production, DNA repair, and survival. NAMPT exists also as an extracellular protein defined in literature as Pre-B cell colony-enhancing factor (PBEF) or as an adipokine called visfatin. Different type of cells are able to release this protein, but its role as a cytokine is still unknown. Emerging data implicate eNAMPT in the pathogenesis of a number of different human diseases that share an inflammatory basis, such as rheumatoid arthritis, type 2 diabetes, acute life-threatening processes such as acute lung injury, sepsis, and tumorigenesis. In the tumour microenvironment, e-NAMPT induces monocyte polarization to M2 macrophages secreting tumor-promoting cytokines and inhibiting T-cell responses rendering this pleiotropic molecule a novel player in tumor/host cross-talk. The function of NAMPT in MPN-associated myelofibrosis biology is completely unknown
Aims
Here we examined plasma levels of eNAMPT in patients with MPN-associated myelofibrosis and their effects on disease phenotype and outcomes. We also studied the concordance of eNAMPT levels with the marker of general inflammation high-sensitivity C-reactive protein (hs-CRP).
Methods
A total of 333 MPN-associated myelofibrosis patients (187 males and 146 females) and 31 age- and gender-matched normal-weight controls were enrolled in the study. The control group was selected among the general population excluding individuals with a body mass index greater than 25. At study entrance, all participants gave their informed consent, and study protocol was approved by the Ethics Committee of our Hospital before implementation. Since there is no accepted definition of disease severity, we evaluated a 'severity score' by indexing leukocytosis, thrombocytosis, and splenomegaly (myeloproliferation index), and anemia, leukopenia, and thrombocytopenia (myelodepletion index) Levels of eNAMPT and hs-CRP were simultaneously assayed in 209 MPN-associated myelofibrosis patients. Twenty-four polycythemia vera or essential thrombocythemia patients were used as controls. eNAMPT levels were measured using a commercial immunoassay kit (BioPlex, BioRad Hercules, CA, USA) according to manufacturer instructions. All samples were assayed in duplicate.
Results
In the 333 MPN-associated myelofibrosis patients enrolled in the study main body, risk stratification according to the IPSS/DIPSS prognostic scoring system showed a predominance of low and intermediate I risk classes (74% of the patients). The severity score of the disease based on spleen size and hematological parameters measured at the time of eNAMPT analysis ranged from 0 to 6 with a median value of 3. The “myeloproliferation index” (range 0 to 4) had a median value of 3 and was equal to or lower than 1 in 39 patients (46.4%), while the “myelodepletion index” (range 0 to 4) had a median value of 2 and was equal to or lower than 1 in 34 patients (40.5%). eNAMPT was over expressed in MPN-associated myelofibrosis (n=333, median 1,487 ng/L, range 81-96,031) compared to healthy subjects (n=31, median 268 ng/L, range 81-4,981; P=0.001). There was no difference in the median eNAMPT level between patients with PMF and post-PV or post-ET myelofibrosis. eNAMPT expression was correlated with higher white blood cell count (R=0.13;P=0.029), higher hemoglobin (R=0.20;P<0.001) and higher platelet count (R=0.25;P=<0.001), suggesting that eNAMPT is an indispensable permissive agent for myeloproliferation of MPN-associated myelofibrosis. In 209 patients with MPN-associated myelofibrosis we simultaneously assayed eNAMPT and hs-CRP. Patients with MPN-associated myelofibrosis had higher levels of hs-CRP than healthy controls (median, 0.15 ng/µl, range, 0.02 to 11.4). However, the individual values of eNAMPT were not correlated with those of hs-CRP level, suggesting that eNAMPT in MPN-associated myelofibrosis does not behave as a canonical inflammatory cytokine. In addition, higher levels of eNAMPT predicted longer time to blast transformation, and protected against progression towards thrombocytopenia and large splenomegaly.
Conclusion
In conclusion, in MPN-associated myelofibrosis high levels of eNAMPT mark the myeloproliferative potential and, at variance with a high number of cancers, are protective against disease progression.
Session topic: E-poster
Keyword(s): Inflammation, Myelofibrosis
Abstract: E1335
Type: Eposter Presentation
Background
Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a clonal, neoplastic disorder of the hematopoietic stem cells, in which inflammation and immune dysregulation play an important role. Somatic mutations of JAK2 (JAK2V617F), CALR or MPL genes ar pathogenetically linked to the disorder. JAK-STAT pathway activation is the main mechanism of myeloproliferation; however, available evidence indicates that inflammatory/immune mechanisms play an important role in the phenotype of MPN-associated myelofibrosis by increased production of inflammatory cytokines and reduced number of regulatory T-cells. Nicotinamide phosphoribosyltransferase (NAMPT), intracellularly, is an enzyme that converts nicotinamide into nicotinamide mononucleotide, precursor of nicotinamide adenine dinucleotide (NAD+), which is essential for cellular metabolism, energy production, DNA repair, and survival. NAMPT exists also as an extracellular protein defined in literature as Pre-B cell colony-enhancing factor (PBEF) or as an adipokine called visfatin. Different type of cells are able to release this protein, but its role as a cytokine is still unknown. Emerging data implicate eNAMPT in the pathogenesis of a number of different human diseases that share an inflammatory basis, such as rheumatoid arthritis, type 2 diabetes, acute life-threatening processes such as acute lung injury, sepsis, and tumorigenesis. In the tumour microenvironment, e-NAMPT induces monocyte polarization to M2 macrophages secreting tumor-promoting cytokines and inhibiting T-cell responses rendering this pleiotropic molecule a novel player in tumor/host cross-talk. The function of NAMPT in MPN-associated myelofibrosis biology is completely unknown
Aims
Here we examined plasma levels of eNAMPT in patients with MPN-associated myelofibrosis and their effects on disease phenotype and outcomes. We also studied the concordance of eNAMPT levels with the marker of general inflammation high-sensitivity C-reactive protein (hs-CRP).
Methods
A total of 333 MPN-associated myelofibrosis patients (187 males and 146 females) and 31 age- and gender-matched normal-weight controls were enrolled in the study. The control group was selected among the general population excluding individuals with a body mass index greater than 25. At study entrance, all participants gave their informed consent, and study protocol was approved by the Ethics Committee of our Hospital before implementation. Since there is no accepted definition of disease severity, we evaluated a 'severity score' by indexing leukocytosis, thrombocytosis, and splenomegaly (myeloproliferation index), and anemia, leukopenia, and thrombocytopenia (myelodepletion index) Levels of eNAMPT and hs-CRP were simultaneously assayed in 209 MPN-associated myelofibrosis patients. Twenty-four polycythemia vera or essential thrombocythemia patients were used as controls. eNAMPT levels were measured using a commercial immunoassay kit (BioPlex, BioRad Hercules, CA, USA) according to manufacturer instructions. All samples were assayed in duplicate.
Results
In the 333 MPN-associated myelofibrosis patients enrolled in the study main body, risk stratification according to the IPSS/DIPSS prognostic scoring system showed a predominance of low and intermediate I risk classes (74% of the patients). The severity score of the disease based on spleen size and hematological parameters measured at the time of eNAMPT analysis ranged from 0 to 6 with a median value of 3. The “myeloproliferation index” (range 0 to 4) had a median value of 3 and was equal to or lower than 1 in 39 patients (46.4%), while the “myelodepletion index” (range 0 to 4) had a median value of 2 and was equal to or lower than 1 in 34 patients (40.5%). eNAMPT was over expressed in MPN-associated myelofibrosis (n=333, median 1,487 ng/L, range 81-96,031) compared to healthy subjects (n=31, median 268 ng/L, range 81-4,981; P=0.001). There was no difference in the median eNAMPT level between patients with PMF and post-PV or post-ET myelofibrosis. eNAMPT expression was correlated with higher white blood cell count (R=0.13;P=0.029), higher hemoglobin (R=0.20;P<0.001) and higher platelet count (R=0.25;P=<0.001), suggesting that eNAMPT is an indispensable permissive agent for myeloproliferation of MPN-associated myelofibrosis. In 209 patients with MPN-associated myelofibrosis we simultaneously assayed eNAMPT and hs-CRP. Patients with MPN-associated myelofibrosis had higher levels of hs-CRP than healthy controls (median, 0.15 ng/µl, range, 0.02 to 11.4). However, the individual values of eNAMPT were not correlated with those of hs-CRP level, suggesting that eNAMPT in MPN-associated myelofibrosis does not behave as a canonical inflammatory cytokine. In addition, higher levels of eNAMPT predicted longer time to blast transformation, and protected against progression towards thrombocytopenia and large splenomegaly.
Conclusion
In conclusion, in MPN-associated myelofibrosis high levels of eNAMPT mark the myeloproliferative potential and, at variance with a high number of cancers, are protective against disease progression.
Session topic: E-poster
Keyword(s): Inflammation, Myelofibrosis
Type: Eposter Presentation
Background
Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a clonal, neoplastic disorder of the hematopoietic stem cells, in which inflammation and immune dysregulation play an important role. Somatic mutations of JAK2 (JAK2V617F), CALR or MPL genes ar pathogenetically linked to the disorder. JAK-STAT pathway activation is the main mechanism of myeloproliferation; however, available evidence indicates that inflammatory/immune mechanisms play an important role in the phenotype of MPN-associated myelofibrosis by increased production of inflammatory cytokines and reduced number of regulatory T-cells. Nicotinamide phosphoribosyltransferase (NAMPT), intracellularly, is an enzyme that converts nicotinamide into nicotinamide mononucleotide, precursor of nicotinamide adenine dinucleotide (NAD+), which is essential for cellular metabolism, energy production, DNA repair, and survival. NAMPT exists also as an extracellular protein defined in literature as Pre-B cell colony-enhancing factor (PBEF) or as an adipokine called visfatin. Different type of cells are able to release this protein, but its role as a cytokine is still unknown. Emerging data implicate eNAMPT in the pathogenesis of a number of different human diseases that share an inflammatory basis, such as rheumatoid arthritis, type 2 diabetes, acute life-threatening processes such as acute lung injury, sepsis, and tumorigenesis. In the tumour microenvironment, e-NAMPT induces monocyte polarization to M2 macrophages secreting tumor-promoting cytokines and inhibiting T-cell responses rendering this pleiotropic molecule a novel player in tumor/host cross-talk. The function of NAMPT in MPN-associated myelofibrosis biology is completely unknown
Aims
Here we examined plasma levels of eNAMPT in patients with MPN-associated myelofibrosis and their effects on disease phenotype and outcomes. We also studied the concordance of eNAMPT levels with the marker of general inflammation high-sensitivity C-reactive protein (hs-CRP).
Methods
A total of 333 MPN-associated myelofibrosis patients (187 males and 146 females) and 31 age- and gender-matched normal-weight controls were enrolled in the study. The control group was selected among the general population excluding individuals with a body mass index greater than 25. At study entrance, all participants gave their informed consent, and study protocol was approved by the Ethics Committee of our Hospital before implementation. Since there is no accepted definition of disease severity, we evaluated a 'severity score' by indexing leukocytosis, thrombocytosis, and splenomegaly (myeloproliferation index), and anemia, leukopenia, and thrombocytopenia (myelodepletion index) Levels of eNAMPT and hs-CRP were simultaneously assayed in 209 MPN-associated myelofibrosis patients. Twenty-four polycythemia vera or essential thrombocythemia patients were used as controls. eNAMPT levels were measured using a commercial immunoassay kit (BioPlex, BioRad Hercules, CA, USA) according to manufacturer instructions. All samples were assayed in duplicate.
Results
In the 333 MPN-associated myelofibrosis patients enrolled in the study main body, risk stratification according to the IPSS/DIPSS prognostic scoring system showed a predominance of low and intermediate I risk classes (74% of the patients). The severity score of the disease based on spleen size and hematological parameters measured at the time of eNAMPT analysis ranged from 0 to 6 with a median value of 3. The “myeloproliferation index” (range 0 to 4) had a median value of 3 and was equal to or lower than 1 in 39 patients (46.4%), while the “myelodepletion index” (range 0 to 4) had a median value of 2 and was equal to or lower than 1 in 34 patients (40.5%). eNAMPT was over expressed in MPN-associated myelofibrosis (n=333, median 1,487 ng/L, range 81-96,031) compared to healthy subjects (n=31, median 268 ng/L, range 81-4,981; P=0.001). There was no difference in the median eNAMPT level between patients with PMF and post-PV or post-ET myelofibrosis. eNAMPT expression was correlated with higher white blood cell count (R=0.13;P=0.029), higher hemoglobin (R=0.20;P<0.001) and higher platelet count (R=0.25;P=<0.001), suggesting that eNAMPT is an indispensable permissive agent for myeloproliferation of MPN-associated myelofibrosis. In 209 patients with MPN-associated myelofibrosis we simultaneously assayed eNAMPT and hs-CRP. Patients with MPN-associated myelofibrosis had higher levels of hs-CRP than healthy controls (median, 0.15 ng/µl, range, 0.02 to 11.4). However, the individual values of eNAMPT were not correlated with those of hs-CRP level, suggesting that eNAMPT in MPN-associated myelofibrosis does not behave as a canonical inflammatory cytokine. In addition, higher levels of eNAMPT predicted longer time to blast transformation, and protected against progression towards thrombocytopenia and large splenomegaly.
Conclusion
In conclusion, in MPN-associated myelofibrosis high levels of eNAMPT mark the myeloproliferative potential and, at variance with a high number of cancers, are protective against disease progression.
Session topic: E-poster
Keyword(s): Inflammation, Myelofibrosis
{{ help_message }}
{{filter}}