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The molecular landscape of childhood myeloproliferative neoplasms
Leukemia Research 38 (2014) 997–998
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Open Forum The molecular landscape of childhood myeloproliferative neoplasms
a r t i c l e
i n f o
Keywords: Myeloproliferative neoplasms Childhood JAK2 V617F CALR
a b s t r a c t The classical myeloproliferative neoplasms (MPN) are comparatively uncommon in children and display a degree of mutational naivety if considering the high frequency of known MPN driver events observed in the corresponding adult diseases. Whole exome sequencing has unravelled much of the underlying molecular complexity of MPN in adult patients yet less is known of the pathogenetic mechanisms when these diseases occur in childhood. It is proposed that such methodological approaches will contribute significant insights into the molecular landscape of childhood MPN that may in turn impact on understanding the pathophysiology of disease in their adult counterparts. © 2014 Elsevier Ltd. All rights reserved.
The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) of polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are predominantly adult diseases characterised physiologically by an over-production of mature haematopoietic cells and clinically by thrombotic and/or haemorrhagic complications and the potential to transform to acute leukaemia. MPNs are also observed in the paediatric population but in these instances, the MPN possesses several distinct characteristics when compared to their adult counterparts: 1. Sporadic MPNs are uncommon in children with an incidence approximately one hundred fold lower than that of adults suggesting an alternative aetiology of the disease in these cases [1,2]. 2. A pre-natal origin of the driver JAK2 V617F mutation has been established in both childhood PV and ET [3,4]. Demonstration of the mutation in antenatal blood spots supports the hypothesis that in these young MPN patients, the JAK2 V617F is acquired early in foetal haematopoietic development with subsequent expansion of the abnormal clone occurring in tandem with normal foetal and post-natal haematopoiesis. If additional events are necessary for the development of clinically overt disease, then these events too, must be acquired early in life. This suggests that fewer genetic lesions are required to result in a clinical phenotype in children and consequently that childhood MPN is more genetically naïve as compared to adult MPN. 3. Acquisition and accumulation of further genetic events over time are implicit in both myelofibrotic and leukaemic transformation of MPN yet the incidence of these processes is lower in childhood MPN than that observed in adults, even with substantial follow up [5]. Again, these observations lend more evidence for a simpler genetic composition of childhood MPN. 4. In both childhood PV and ET, the prevalence of the JAK2 V617F mutation is lower when compared to that in adults [5,6]. The http://dx.doi.org/10.1016/j.leukres.2014.06.003 0145-2126/© 2014 Elsevier Ltd. All rights reserved.
rising incidence of JAK2 V617F-positivity with age implicates an increasing, age-related, underlying genetic instability to be at least partially responsible in facilitating acquisition of this and other MPN-associated mutations. 5. Aside from the JAK2 V617F, alternative driver mutations associated with adult MPN, such as those of MPL exon 10 and TET2 have been seldom reported in sporadic childhood MPN [6,7]. Recently, whole exome sequencing approaches have identified mutations of CALR exon nine in adult MPN. These insertion and/or deletion mutations appear to be initiating events and represent the second most common mutations in adult MPN, being present in approximately 70–80% of JAK2 and MPL un-mutated ET and PMF [8,9]. It must also be noted that a significant minority of adult ET and PMF patients have no evident JAK2, MPL, or CALR mutations. To date, one single-centre study has reported that CALR mutations are uncommon in childhood ET [10] further speculating the existence of distinct molecular landscapes of adult and childhood MPN. Whole exome sequencing has furthermore demonstrated the underlying mutational complexity of adult MPN with a median of 6.5 mutations in PV and ET and 13 mutations in PMF [9]. Such methodological approaches, if applied to childhood MPN, would be likely to reveal the molecular origins; of particular interest would be those cases with no documented JAK2, CALR or MPL driver mutations. As the incidence of childhood MPN is low, with most cohorts reported from either single institution or national studies, considerable collaboration would be required to recruit sufficient patients for meaningful study and analysis. A registry of those patients with a clearly defined diagnosis of MPN linked to a repository for disease and constitutional control material could be established by the centre(s) able to perform such investigations. The discovery of JAK2 mutations in MPN has led to the rapid development of agents capable of abrogating the disrupted,
998
Open Forum / Leukemia Research 38 (2014) 997–998
proliferative signalling potentiated by this abnormal protein. If the postulated molecular landscape in childhood MPN proves to be less complex than in the corresponding adult disease, identification and characterisation of the as yet unknown driver events may provide targets of therapeutic intervention potentially applicable to all MPN. Conflict of interest statement The authors declare no conflict of interest. References [1] Teofili L, Foà R, Giona F, et al. Childhood polycythemia vera and essential thrombocythemia: does their pathogenesis overlap with that of adult patients. Haematologica 2008;93:169–72. [2] Fu R, Zhang L, Yang R. Paediatric essential thrombocythaemia: clinical and molecular features, diagnosis and treatment. Br J Haematol 2013;163:295–302. [3] Kelly K, McMahon C, Langabeer S, et al. Congenital JAK2 V617F polycythemia vera: where does the genotype-phenotype diversity end. Blood 2008;112:4356–7. [4] Langabeer SE, Haslam K, McMahon C. A prenatal origin of childhood essential thrombocythaemia. Br J Haematol 2013;163:676–8. [5] Giona F, Teofili L, Moleti ML, et al. Thrombocythemia and polycythemia in patients younger than 20 years at diagnosis: clinical and biological features, treatment, and long-term outcome. Blood 2012;119:2219–27. [6] Ismael O, Shimada A, Hama A, et al. Mutations profile of polycythemia vera and essential thrombocythemia among Japanese children. Pediatr Blood Cancer 2012;59:530–5.
[7] Farruggia P, D’Angelo P, La Rosa M, et al. MPL W515L mutation in pediatric essential thrombocythemia. Pediatr Blood Cancer 2013;60:e52–4. [8] Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379–90. [9] Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391–405. [10] Langabeer SE, Haslam K, McMahon C. CALR mutations are rare in childhood essential thrombocythemia. Pediatr Blood Cancer 2014;61:1523.
Stephen E. Langabeer ∗ Karl Haslam Cancer Molecular Diagnostics, St. James’s Hospital, Dublin, Ireland Corrina McMahon Department of Haematology, Our Lady’s Children’s Hospital, Dublin, Ireland Corresponding author at: Cancer Molecular Diagnostics, Central Pathology Laboratory, St. James’s Hospital, Dublin 8, Ireland. Tel.: +353 1 4103576; fax: +353 1 4103513. E-mail address: [email protected] (S.E. Langabeer) 13 May 2014 Available online 12 June 2014
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Open Forum The molecular landscape of childhood myeloproliferative neoplasms
a r t i c l e
i n f o
Keywords: Myeloproliferative neoplasms Childhood JAK2 V617F CALR
a b s t r a c t The classical myeloproliferative neoplasms (MPN) are comparatively uncommon in children and display a degree of mutational naivety if considering the high frequency of known MPN driver events observed in the corresponding adult diseases. Whole exome sequencing has unravelled much of the underlying molecular complexity of MPN in adult patients yet less is known of the pathogenetic mechanisms when these diseases occur in childhood. It is proposed that such methodological approaches will contribute significant insights into the molecular landscape of childhood MPN that may in turn impact on understanding the pathophysiology of disease in their adult counterparts. © 2014 Elsevier Ltd. All rights reserved.
The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) of polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are predominantly adult diseases characterised physiologically by an over-production of mature haematopoietic cells and clinically by thrombotic and/or haemorrhagic complications and the potential to transform to acute leukaemia. MPNs are also observed in the paediatric population but in these instances, the MPN possesses several distinct characteristics when compared to their adult counterparts: 1. Sporadic MPNs are uncommon in children with an incidence approximately one hundred fold lower than that of adults suggesting an alternative aetiology of the disease in these cases [1,2]. 2. A pre-natal origin of the driver JAK2 V617F mutation has been established in both childhood PV and ET [3,4]. Demonstration of the mutation in antenatal blood spots supports the hypothesis that in these young MPN patients, the JAK2 V617F is acquired early in foetal haematopoietic development with subsequent expansion of the abnormal clone occurring in tandem with normal foetal and post-natal haematopoiesis. If additional events are necessary for the development of clinically overt disease, then these events too, must be acquired early in life. This suggests that fewer genetic lesions are required to result in a clinical phenotype in children and consequently that childhood MPN is more genetically naïve as compared to adult MPN. 3. Acquisition and accumulation of further genetic events over time are implicit in both myelofibrotic and leukaemic transformation of MPN yet the incidence of these processes is lower in childhood MPN than that observed in adults, even with substantial follow up [5]. Again, these observations lend more evidence for a simpler genetic composition of childhood MPN. 4. In both childhood PV and ET, the prevalence of the JAK2 V617F mutation is lower when compared to that in adults [5,6]. The http://dx.doi.org/10.1016/j.leukres.2014.06.003 0145-2126/© 2014 Elsevier Ltd. All rights reserved.
rising incidence of JAK2 V617F-positivity with age implicates an increasing, age-related, underlying genetic instability to be at least partially responsible in facilitating acquisition of this and other MPN-associated mutations. 5. Aside from the JAK2 V617F, alternative driver mutations associated with adult MPN, such as those of MPL exon 10 and TET2 have been seldom reported in sporadic childhood MPN [6,7]. Recently, whole exome sequencing approaches have identified mutations of CALR exon nine in adult MPN. These insertion and/or deletion mutations appear to be initiating events and represent the second most common mutations in adult MPN, being present in approximately 70–80% of JAK2 and MPL un-mutated ET and PMF [8,9]. It must also be noted that a significant minority of adult ET and PMF patients have no evident JAK2, MPL, or CALR mutations. To date, one single-centre study has reported that CALR mutations are uncommon in childhood ET [10] further speculating the existence of distinct molecular landscapes of adult and childhood MPN. Whole exome sequencing has furthermore demonstrated the underlying mutational complexity of adult MPN with a median of 6.5 mutations in PV and ET and 13 mutations in PMF [9]. Such methodological approaches, if applied to childhood MPN, would be likely to reveal the molecular origins; of particular interest would be those cases with no documented JAK2, CALR or MPL driver mutations. As the incidence of childhood MPN is low, with most cohorts reported from either single institution or national studies, considerable collaboration would be required to recruit sufficient patients for meaningful study and analysis. A registry of those patients with a clearly defined diagnosis of MPN linked to a repository for disease and constitutional control material could be established by the centre(s) able to perform such investigations. The discovery of JAK2 mutations in MPN has led to the rapid development of agents capable of abrogating the disrupted,
998
Open Forum / Leukemia Research 38 (2014) 997–998
proliferative signalling potentiated by this abnormal protein. If the postulated molecular landscape in childhood MPN proves to be less complex than in the corresponding adult disease, identification and characterisation of the as yet unknown driver events may provide targets of therapeutic intervention potentially applicable to all MPN. Conflict of interest statement The authors declare no conflict of interest. References [1] Teofili L, Foà R, Giona F, et al. Childhood polycythemia vera and essential thrombocythemia: does their pathogenesis overlap with that of adult patients. Haematologica 2008;93:169–72. [2] Fu R, Zhang L, Yang R. Paediatric essential thrombocythaemia: clinical and molecular features, diagnosis and treatment. Br J Haematol 2013;163:295–302. [3] Kelly K, McMahon C, Langabeer S, et al. Congenital JAK2 V617F polycythemia vera: where does the genotype-phenotype diversity end. Blood 2008;112:4356–7. [4] Langabeer SE, Haslam K, McMahon C. A prenatal origin of childhood essential thrombocythaemia. Br J Haematol 2013;163:676–8. [5] Giona F, Teofili L, Moleti ML, et al. Thrombocythemia and polycythemia in patients younger than 20 years at diagnosis: clinical and biological features, treatment, and long-term outcome. Blood 2012;119:2219–27. [6] Ismael O, Shimada A, Hama A, et al. Mutations profile of polycythemia vera and essential thrombocythemia among Japanese children. Pediatr Blood Cancer 2012;59:530–5.
[7] Farruggia P, D’Angelo P, La Rosa M, et al. MPL W515L mutation in pediatric essential thrombocythemia. Pediatr Blood Cancer 2013;60:e52–4. [8] Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013;369:2379–90. [9] Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391–405. [10] Langabeer SE, Haslam K, McMahon C. CALR mutations are rare in childhood essential thrombocythemia. Pediatr Blood Cancer 2014;61:1523.
Stephen E. Langabeer ∗ Karl Haslam Cancer Molecular Diagnostics, St. James’s Hospital, Dublin, Ireland Corrina McMahon Department of Haematology, Our Lady’s Children’s Hospital, Dublin, Ireland Corresponding author at: Cancer Molecular Diagnostics, Central Pathology Laboratory, St. James’s Hospital, Dublin 8, Ireland. Tel.: +353 1 4103576; fax: +353 1 4103513. E-mail address: [email protected] (S.E. Langabeer) 13 May 2014 Available online 12 June 2014