doi:10.1111/ejh.12437
European Journal of Haematology 94 (96–98)
EDITORIAL
Perspectives on the increased risk of second cancer in patients with essential thrombocythemia, polycythemia vera and myelofibrosis Hans Carl Hasselbalch Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark
In recent years, several studies have evidenced that the Philadelphia-negative myeloproliferative neoplasms – essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) (MPNs) – are associated with an increased risk of chronic inflammatory diseases, autoimmune diseases, and second cancers as well (1, 2). Furthermore, most recently it has been hypothesized that chronic inflammation may be a trigger and driver of premature atherosclerosis, clonal evolution, and second cancer in patients with MPNs (3). In this perspective, the MPNs have also been described as ‘A Human Inflammation Model for Cancer Development’ (4), as the MPNs per se generate inflammatory products, which in a self-perpetuating vicious circle may facilitate clonal evolution (3–5). Considering the above and the general contention that chronic inflammation may be a major contributing factor for cancer development and progression (6, 7) the reports on an increased risk of second cancer in patients with MPNs are only supportive of a link between chronic inflammation and the development of cancer in patients with MPNs as well (3–5). Previous studies on the risk of second cancer in MPNs have assessed the cancer risk after the MPN diagnosis (2). In this issue of European Journal of Haematology, Pettersson and collegues provide highly important novel information on the risk of second cancer in patients with MPNs (8). The authors report a large epidemiological study, covering a 3-yr period prior to the MPN diagnosis, including 2213 patients with ET, PV, and PMF. Prior to the MPN diagnosis, this study has shown an increased number of MPN patients with cancer as compared to the general population. The observation of an increased risk of cancer in patients with MPN prior to the MPN diagnosis raises several important questions in regard to causality and topics for future research. Firstly, it is intriguing to consider the possibility that a large proportion of patients with a diagnosis of MPN may actually have carried the disease for several years (5-10-15 yr?) before the MPN diagnosis. Conceiving a long pre-MPN diagnosis phase to exist – a notion, which is supported by a most recent study, showing that increased JAK2V617F
Correspondence Hans Carl Hasselbalch, Department of Hematology, Roskilde Hospital, University of Copenhagen. Tel: +45 26223678; Fax: +46353439; e-mail: [email protected]
96
somatic mutation burden is associated with myeloproliferative neoplasm progression rate in the general population (9) – the increased risk of second cancer even prior to the MPN diagnosis might be explained by an impaired ‘tumor immune surveillance’ (3) consequent to a steady expansion of the MPN clone giving rise to a low-grade chronic inflammatory state and immune deregulation (10–12) with elevated levels of several inflammatory cytokines, which have most recently reviewed (5). A persistent but steadily increasing chronic inflammation drive in the pre-MPN diagnosis phase, being subsequently perpetuated by the MPN clone per se (3–5), may constitute the ‘fertile ground’ for mutagenesis and MPN evolution (4). In the context of an inflammation-mediated defective ‘tumor immune surveillance’ in MPNs, the release of the immunosuppressive cytokines vascular endothelial growth factor (VEGF) and transforming growth factor (TGFbeta) may be of particular importance for the increased risk of cancer development, both cytokines inducing qualitative and quantitative alterations in immune cells of utmost importance for intact tumor immune surveillance (e.g., dendritic cells, cytotoxic T cells, regulatory T cells, and NK cells) (3– 5). Secondly, the JAK2V617F mutation has been shown to induce accumulation of reactive oxygen species (ROS) in haematopoietic stem cells (13), which is associated with genomic instability and accordingly a risk of clonal evolution. This propensity may not only imply clonal MPN expansion but also – in general – an increased risk of any cancer, which associates with the JAK2V617F mutation in the general population (14). Thirdly, the MPNs and the systemic inflammatory response that they arise may facilitate the evolution of cancers at other sites. Thus, tumors have been shown to induce complex DNA damage in distant tissues in vivo (15). In this study, it was demonstrated that the presence of a tumor may induce a chronic inflammatory response, leading to increased systemic levels of DNA damage (15). Being ‘systemic cancers’ of the bone marrow and the blood, this propensity may be even more pronounced in patients with MPNs. Of note, considering that both TGFbeta and ROS are elevated in MPNs and both are capable of inducing oxidative DNA lesions, potentially also at ‘distant sites’, one may speculate whether the MPNs – by eliciting a perpetuating and persistent level of systemic inflammation – are associated with an increased cancer risk due to these inflammation-mediated mechanisms as well. Fourthly,
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Editorial
having an increased risk of second cancer – both prior and after the MPN diagnosis – the time is ripe to consider whether this novel information should already now be translated into recommendations for ‘cancer screening’ at the time of the MPN diagnosis. In this context, the increased risk of cancer in patients with MPNs may just add other inflammatory diseases (ET, PV, MF) to the list of chronic inflammatory diseases, which are associated with an increased risk of second cancer. Fifthly, this study may also give rise to additional concern in regard to the use of hydroxyurea (HU) in patients with MPNs, considering that HU inhibits DNA repair and a defective DNA-repair mechanism is one of several important factors, facilitating cancer development and its progression as well. Sixthly, given that the increased risk of cancer prior to MPN diagnosis actually reflects an impaired ‘tumor immune surveillance’, this novel knowledge is certainly supportive of using immune-enhancing therapy in MPNs, aiming at restoring the defective tumor immune surveillance system (3–5, 16–18). Interferon-alpha2 (IFN) is such an agent that potently enhances the efficacy of highly important immune cells involved in ‘tumor immune surveillance’, for example cytotoxic T cells, dendritic cells, and NK cells (3–5, 16–18). Accordingly, the increased risk of cancer already prior to MPN diagnosis is only supportive of using IFN from the time of diagnosis in patients with ET, PV, and in the early hypercellular myelofibrosis phase (3–5, 16, 18). For all the above reasons, the study by Pettersson et al. (8) is of utmost importance and hopefully will encourage to additional clinical and epidemiological studies, confirming and extending their observations on the increased cancer risk prior to the MPN diagnosis. Furthermore, clinical, molecular and immune cell studies are needed in IFN- and HU-treated MPN patients with and without second cancer in order to explore the basic mechanisms responsible for the increased risk of second cancer and to unravel the complexity of immune deregulation in patients with MPN – both prior and during treatment with conventional (e.g., HU, IFN) and novel therapies (e.g., JAK inhibitors). As JAK inhibition may be a future treatment option not only in myelofibrosis but also in a proportion of patients with ET and PV, studies on the impact of JAK inhibitor therapy on immune cells and accordingly ‘tumor immune surveillance’ and risk of second cancer are urgently needed as well. By decreasing inflammatory cytokines, JAK inhibitor therapy (e.g., ruxolitinib) may theoretically prohibit the inflammatory drive for cancer initiation. In addition, JAK inhibition also impairs dendritic cell differentiation and function resulting in impaired T-cell activation (19), which might add to the pronounced anti-inflammatory and immunomodulating activity of JAK inhibitors in myelofibrosis and autoimmune diseases. Hopefully, using IFN in the early MPN phase (ET and PV) may not only prohibit clonal evolution and disease progression but also – by restoring defective tumor immune surveillance – may have the potential of diminishing the increased risk of second cancer in MPNs (3). In the
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
context of ‘The Platelet-Cancer Loop’, normalization of elevated platelets counts by IFN and dampening chronic inflammation and in vivo leukocyte and platelet activation by statins may be of particular importance to minimize the increased cancer invasiveness and metastatic potential which are associated with cancer-associated thrombocytosis in the general population and likely also in patients with MPNs and second cancer (20). In this perspective, IFN and a statin may be a rational combination therapy to be used in the future, taking into account that both agents impair MPN cell growth (16, 18, 21, 22), and statin treatment – in addition – has been shown to reduce cancer-related mortality as well (23). References 1. Kristinsson SY, Landgren O, Samuelsson J, Bjorkholm M, Goldin LR. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica 2010;7:1216–20. 2. Frederiksen H, Farkas DK, Christiansen CF, Hasselbalch HC, Sorensen HT. Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study. Blood 2011;118:6515–20. 3. Hasselbalch HC. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood 2012;119:3219–25. 4. Hasselbalch HC. Chronic inflammation as a promoter of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk Res 2013;37:214–20. 5. Hasselbalch HC. The role of cytokines in the initiation and progression of myelofibrosis. Cytokine Growth Factor Rev 2013;24:133–45. 6. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357:539–45. 7. Mantovani A, Garlanda C, Allavena P. Molecular pathways and targets in cancer-related inflammation. Ann Med 2010;42:161–70. 8. Pettersson H, Knutsen H, Holmberg E, Andreasson B. Increased incidence of another cancer in myeloproliferative neoplasms patients at the time of diagnosis. Eur J Haematol 2014. doi: 10.1111/ejh.12410 [Epub ahead of print]. 9. Nielsen C, Bojesen SE, Nordestgaard BG, Kofoed KF, Birgens HS. JAK2V617F somatic mutation in the general population: myeloproliferative neoplasm development and progression rate. Haematologica 2014; pii: haematol.2014.107631. [Epub ahead of print]. 10. Skov V, Larsen TS, Thomassen M, et al. Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: identification of deregulated genes of significance for inflammation and immune surveillance. Leuk Res 2012;36:1387–92. 11. Skov V, Thomassen M, Riley CH, et al. Gene expression profiling with principal component analysis depicts the biological
97
Editorial
12.
13.
14.
15.
16.
17.
98
continuum from essential thrombocythemia over polycythemia vera to myelofibrosis. Exp Hematol 2012;40:771–80. Skov V, Riley CH, Larsen TS, et al. Whole blood transcriptional profiling reveals significant downregulation of HLA class I and II genes in essential thrombocythemia, polycythemia vera and myelofibrosis. Leuk Lymphoma 2013;54: 2269–73. Marty C, Lacout C, Droin N, et al. A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression. Leukemia 2013;27:2187–95. Nielsen C, Birgens HS, Nordestgaard BG, Kjaer L, Bojesen SE. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica 2011;96:450–3. Redon CE, Dickey JS, Nakamura AJ, et al. Tumors induce complex DNA damage in distant proliferative tissues in vivo. Proc Natl Acad Sci USA 2010;107:17992–7. Hasselbalch HC. A new era of interferon-alpha2 in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. Expert Rev Hematol 2011;4:637–55. Riley CH, Hansen M, Brimnes MK, et al. Expansion of circulating CD56bright natural killer cells in patients with JAK2positive chronic myeloproliferative neoplasms during treatment with interferon-alpha. Eur J Haematol 2014. doi: 10.1111/ejh.12420 [Epub ahead of print].
18. Silver RT, Kiladjian JJ, Hasselbalch HC. Interferon in the treatment of essential thrombocythemia, polycythemia vera and myelofibrosis. Expert Rev Hematol 2013;6:49–58. 19. Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013;122:1192–202. 20. Hasselbalch HC. The platelet-cancer loop in myeloproliferative cancer. Is thrombocythemia an enhancer of cancer invasiveness and metastasis in essential thrombocythemia, polycythemia vera and myelofibrosis? Leuk Res 2014;pii: S0145-2126(14)00223-9. doi: 10.1016/j.leukres.2014.07.006 [Epub ahead of print]. 21. Griner LN, McGraw KL, Johnson JO, List AF, Reuther GW. A mechanistic rationale for the use of statins to enhance JAK2 inhibitor therapy in MPN [abstract]. Blood (ASH Annual Meeting Abstracts) 2011;118:Abstract No. 2816. 22. Griner LN, McGraw KL, Johnson JO, List AF, Reuther GW. JAK2-V617F-mediated signaling is dependent on the lipid rafts and statins inhibit JAK2-V617F-dependent cell growth. Br J Haematol 2013;160:177–87. 23. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med 2013;368:576–7.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Copyright of European Journal of Haematology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
European Journal of Haematology 94 (96–98)
EDITORIAL
Perspectives on the increased risk of second cancer in patients with essential thrombocythemia, polycythemia vera and myelofibrosis Hans Carl Hasselbalch Department of Hematology, Roskilde Hospital, University of Copenhagen, Roskilde, Denmark
In recent years, several studies have evidenced that the Philadelphia-negative myeloproliferative neoplasms – essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) (MPNs) – are associated with an increased risk of chronic inflammatory diseases, autoimmune diseases, and second cancers as well (1, 2). Furthermore, most recently it has been hypothesized that chronic inflammation may be a trigger and driver of premature atherosclerosis, clonal evolution, and second cancer in patients with MPNs (3). In this perspective, the MPNs have also been described as ‘A Human Inflammation Model for Cancer Development’ (4), as the MPNs per se generate inflammatory products, which in a self-perpetuating vicious circle may facilitate clonal evolution (3–5). Considering the above and the general contention that chronic inflammation may be a major contributing factor for cancer development and progression (6, 7) the reports on an increased risk of second cancer in patients with MPNs are only supportive of a link between chronic inflammation and the development of cancer in patients with MPNs as well (3–5). Previous studies on the risk of second cancer in MPNs have assessed the cancer risk after the MPN diagnosis (2). In this issue of European Journal of Haematology, Pettersson and collegues provide highly important novel information on the risk of second cancer in patients with MPNs (8). The authors report a large epidemiological study, covering a 3-yr period prior to the MPN diagnosis, including 2213 patients with ET, PV, and PMF. Prior to the MPN diagnosis, this study has shown an increased number of MPN patients with cancer as compared to the general population. The observation of an increased risk of cancer in patients with MPN prior to the MPN diagnosis raises several important questions in regard to causality and topics for future research. Firstly, it is intriguing to consider the possibility that a large proportion of patients with a diagnosis of MPN may actually have carried the disease for several years (5-10-15 yr?) before the MPN diagnosis. Conceiving a long pre-MPN diagnosis phase to exist – a notion, which is supported by a most recent study, showing that increased JAK2V617F
Correspondence Hans Carl Hasselbalch, Department of Hematology, Roskilde Hospital, University of Copenhagen. Tel: +45 26223678; Fax: +46353439; e-mail: [email protected]
96
somatic mutation burden is associated with myeloproliferative neoplasm progression rate in the general population (9) – the increased risk of second cancer even prior to the MPN diagnosis might be explained by an impaired ‘tumor immune surveillance’ (3) consequent to a steady expansion of the MPN clone giving rise to a low-grade chronic inflammatory state and immune deregulation (10–12) with elevated levels of several inflammatory cytokines, which have most recently reviewed (5). A persistent but steadily increasing chronic inflammation drive in the pre-MPN diagnosis phase, being subsequently perpetuated by the MPN clone per se (3–5), may constitute the ‘fertile ground’ for mutagenesis and MPN evolution (4). In the context of an inflammation-mediated defective ‘tumor immune surveillance’ in MPNs, the release of the immunosuppressive cytokines vascular endothelial growth factor (VEGF) and transforming growth factor (TGFbeta) may be of particular importance for the increased risk of cancer development, both cytokines inducing qualitative and quantitative alterations in immune cells of utmost importance for intact tumor immune surveillance (e.g., dendritic cells, cytotoxic T cells, regulatory T cells, and NK cells) (3– 5). Secondly, the JAK2V617F mutation has been shown to induce accumulation of reactive oxygen species (ROS) in haematopoietic stem cells (13), which is associated with genomic instability and accordingly a risk of clonal evolution. This propensity may not only imply clonal MPN expansion but also – in general – an increased risk of any cancer, which associates with the JAK2V617F mutation in the general population (14). Thirdly, the MPNs and the systemic inflammatory response that they arise may facilitate the evolution of cancers at other sites. Thus, tumors have been shown to induce complex DNA damage in distant tissues in vivo (15). In this study, it was demonstrated that the presence of a tumor may induce a chronic inflammatory response, leading to increased systemic levels of DNA damage (15). Being ‘systemic cancers’ of the bone marrow and the blood, this propensity may be even more pronounced in patients with MPNs. Of note, considering that both TGFbeta and ROS are elevated in MPNs and both are capable of inducing oxidative DNA lesions, potentially also at ‘distant sites’, one may speculate whether the MPNs – by eliciting a perpetuating and persistent level of systemic inflammation – are associated with an increased cancer risk due to these inflammation-mediated mechanisms as well. Fourthly,
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Editorial
having an increased risk of second cancer – both prior and after the MPN diagnosis – the time is ripe to consider whether this novel information should already now be translated into recommendations for ‘cancer screening’ at the time of the MPN diagnosis. In this context, the increased risk of cancer in patients with MPNs may just add other inflammatory diseases (ET, PV, MF) to the list of chronic inflammatory diseases, which are associated with an increased risk of second cancer. Fifthly, this study may also give rise to additional concern in regard to the use of hydroxyurea (HU) in patients with MPNs, considering that HU inhibits DNA repair and a defective DNA-repair mechanism is one of several important factors, facilitating cancer development and its progression as well. Sixthly, given that the increased risk of cancer prior to MPN diagnosis actually reflects an impaired ‘tumor immune surveillance’, this novel knowledge is certainly supportive of using immune-enhancing therapy in MPNs, aiming at restoring the defective tumor immune surveillance system (3–5, 16–18). Interferon-alpha2 (IFN) is such an agent that potently enhances the efficacy of highly important immune cells involved in ‘tumor immune surveillance’, for example cytotoxic T cells, dendritic cells, and NK cells (3–5, 16–18). Accordingly, the increased risk of cancer already prior to MPN diagnosis is only supportive of using IFN from the time of diagnosis in patients with ET, PV, and in the early hypercellular myelofibrosis phase (3–5, 16, 18). For all the above reasons, the study by Pettersson et al. (8) is of utmost importance and hopefully will encourage to additional clinical and epidemiological studies, confirming and extending their observations on the increased cancer risk prior to the MPN diagnosis. Furthermore, clinical, molecular and immune cell studies are needed in IFN- and HU-treated MPN patients with and without second cancer in order to explore the basic mechanisms responsible for the increased risk of second cancer and to unravel the complexity of immune deregulation in patients with MPN – both prior and during treatment with conventional (e.g., HU, IFN) and novel therapies (e.g., JAK inhibitors). As JAK inhibition may be a future treatment option not only in myelofibrosis but also in a proportion of patients with ET and PV, studies on the impact of JAK inhibitor therapy on immune cells and accordingly ‘tumor immune surveillance’ and risk of second cancer are urgently needed as well. By decreasing inflammatory cytokines, JAK inhibitor therapy (e.g., ruxolitinib) may theoretically prohibit the inflammatory drive for cancer initiation. In addition, JAK inhibition also impairs dendritic cell differentiation and function resulting in impaired T-cell activation (19), which might add to the pronounced anti-inflammatory and immunomodulating activity of JAK inhibitors in myelofibrosis and autoimmune diseases. Hopefully, using IFN in the early MPN phase (ET and PV) may not only prohibit clonal evolution and disease progression but also – by restoring defective tumor immune surveillance – may have the potential of diminishing the increased risk of second cancer in MPNs (3). In the
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
context of ‘The Platelet-Cancer Loop’, normalization of elevated platelets counts by IFN and dampening chronic inflammation and in vivo leukocyte and platelet activation by statins may be of particular importance to minimize the increased cancer invasiveness and metastatic potential which are associated with cancer-associated thrombocytosis in the general population and likely also in patients with MPNs and second cancer (20). In this perspective, IFN and a statin may be a rational combination therapy to be used in the future, taking into account that both agents impair MPN cell growth (16, 18, 21, 22), and statin treatment – in addition – has been shown to reduce cancer-related mortality as well (23). References 1. Kristinsson SY, Landgren O, Samuelsson J, Bjorkholm M, Goldin LR. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica 2010;7:1216–20. 2. Frederiksen H, Farkas DK, Christiansen CF, Hasselbalch HC, Sorensen HT. Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study. Blood 2011;118:6515–20. 3. Hasselbalch HC. Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood 2012;119:3219–25. 4. Hasselbalch HC. Chronic inflammation as a promoter of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk Res 2013;37:214–20. 5. Hasselbalch HC. The role of cytokines in the initiation and progression of myelofibrosis. Cytokine Growth Factor Rev 2013;24:133–45. 6. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357:539–45. 7. Mantovani A, Garlanda C, Allavena P. Molecular pathways and targets in cancer-related inflammation. Ann Med 2010;42:161–70. 8. Pettersson H, Knutsen H, Holmberg E, Andreasson B. Increased incidence of another cancer in myeloproliferative neoplasms patients at the time of diagnosis. Eur J Haematol 2014. doi: 10.1111/ejh.12410 [Epub ahead of print]. 9. Nielsen C, Bojesen SE, Nordestgaard BG, Kofoed KF, Birgens HS. JAK2V617F somatic mutation in the general population: myeloproliferative neoplasm development and progression rate. Haematologica 2014; pii: haematol.2014.107631. [Epub ahead of print]. 10. Skov V, Larsen TS, Thomassen M, et al. Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: identification of deregulated genes of significance for inflammation and immune surveillance. Leuk Res 2012;36:1387–92. 11. Skov V, Thomassen M, Riley CH, et al. Gene expression profiling with principal component analysis depicts the biological
97
Editorial
12.
13.
14.
15.
16.
17.
98
continuum from essential thrombocythemia over polycythemia vera to myelofibrosis. Exp Hematol 2012;40:771–80. Skov V, Riley CH, Larsen TS, et al. Whole blood transcriptional profiling reveals significant downregulation of HLA class I and II genes in essential thrombocythemia, polycythemia vera and myelofibrosis. Leuk Lymphoma 2013;54: 2269–73. Marty C, Lacout C, Droin N, et al. A role for reactive oxygen species in JAK2 V617F myeloproliferative neoplasm progression. Leukemia 2013;27:2187–95. Nielsen C, Birgens HS, Nordestgaard BG, Kjaer L, Bojesen SE. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica 2011;96:450–3. Redon CE, Dickey JS, Nakamura AJ, et al. Tumors induce complex DNA damage in distant proliferative tissues in vivo. Proc Natl Acad Sci USA 2010;107:17992–7. Hasselbalch HC. A new era of interferon-alpha2 in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. Expert Rev Hematol 2011;4:637–55. Riley CH, Hansen M, Brimnes MK, et al. Expansion of circulating CD56bright natural killer cells in patients with JAK2positive chronic myeloproliferative neoplasms during treatment with interferon-alpha. Eur J Haematol 2014. doi: 10.1111/ejh.12420 [Epub ahead of print].
18. Silver RT, Kiladjian JJ, Hasselbalch HC. Interferon in the treatment of essential thrombocythemia, polycythemia vera and myelofibrosis. Expert Rev Hematol 2013;6:49–58. 19. Heine A, Held SA, Daecke SN, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood 2013;122:1192–202. 20. Hasselbalch HC. The platelet-cancer loop in myeloproliferative cancer. Is thrombocythemia an enhancer of cancer invasiveness and metastasis in essential thrombocythemia, polycythemia vera and myelofibrosis? Leuk Res 2014;pii: S0145-2126(14)00223-9. doi: 10.1016/j.leukres.2014.07.006 [Epub ahead of print]. 21. Griner LN, McGraw KL, Johnson JO, List AF, Reuther GW. A mechanistic rationale for the use of statins to enhance JAK2 inhibitor therapy in MPN [abstract]. Blood (ASH Annual Meeting Abstracts) 2011;118:Abstract No. 2816. 22. Griner LN, McGraw KL, Johnson JO, List AF, Reuther GW. JAK2-V617F-mediated signaling is dependent on the lipid rafts and statins inhibit JAK2-V617F-dependent cell growth. Br J Haematol 2013;160:177–87. 23. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med 2013;368:576–7.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Copyright of European Journal of Haematology is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
