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Editorial
Introduction to a review series on myeloproliferative neoplasms
According to PubMed, the adjective “myeloproliferative” was used for the
first time in the title of a scientific paper by William Dameshek in 1951,
when he published an editorial in Blood entitled, “Some speculations on
the myeloproliferative syndromes.”1 In this article, featured in the recent
Blood Flashback series, Dameshek introduced the concept of myeloproliferative disorders as conditions characterized by excessive proliferation
of hematopoietic precursors in the bone marrow and excessive production
of mature blood cells. He included in this category chronic granulocytic
leukemia, polycythemia vera (PV), idiopathic or agnogenic myeloid
metaplasia of spleen, megakaryocytic leukemia, and erythroleukemia.
Although some of these names are no longer in use, Dameshek’s editorial
represents a remarkable example of visionary leadership.
In 2008, to underscore the clonal nature of myeloproliferative disorders,
the authors of the WHO Classification of Tumours of Haematopoietic and
Lymphoid Tissues introduced the name “myeloproliferative neoplasms”
(MPNs).2 The revised version of this classification includes the following
MPNs3: chronic myeloid leukemia (CML), BCR-ABL11; chronic
neutrophilic leukemia (CNL); PV; primary myelofibrosis (PMF); essential
thrombocythemia (ET); chronic eosinophilic leukemia, not otherwise specified; and MPN, unclassifiable. In addition, the WHO
Classification of Tumours of Haematopoietic and Lymphoid Tissues
comprises the myeloid/lymphoid neoplasms with eosinophilia and
rearrangements of PDGFRA, PDGFRB, FGFR1, or with PCM1-JAK2.
Over recent years, there have been tremendous advances in our
understanding of the genetic basis of MPNs and related myeloid
neoplasms. Milestones in this field include the following discoveries: (1) the FIP1L1-PDGFRA fusion gene in patients with hypereosinophilic syndrome in 20034; (2) the unique JAK2 (V617F)
mutation in patients with classical MPNs in 20055-8; (3) oncogenic
CSF3R mutations in patients with CNL in 20139; and (4) somatic
mutations of CALR in classical MPNs in 2013.10,11
The following series of reviews describes the latest advances in
our understanding of the genetic basis of MPNs and related myeloid
neoplasms, as well as of its clinical relevance:
c
c
c
c
c
William Vainchenker and Robert Kralovics, “Genetic basis and
molecular pathophysiology of classical myeloproliferative neoplasms”
Elisa Rumi and Mario Cazzola, “Diagnosis, risk stratification, and
response evaluation in classical myeloproliferative neoplasms”
Alessandro M. Vannucchi and Claire N. Harrison, “Emerging treatments for classical myeloproliferative neoplasms”
Andreas Reiter and Jason Gotlib, “Myeloid neoplasms with
eosinophilia”
Julia E. Maxson and Jeffrey W. Tyner, “Genomics of chronic
neutrophilic leukemia”
In the first review, Vainchenker and Kralovics examine the genetic
landscape of MPNs. They subdivide mutant genes into MPN drivers and
non-MPN drivers. Through gain-of-function mutations, MPN-driver
genes activate the cytokine receptor/JAK2 pathway and their downstream effectors. On the other hand, through loss-of-function mutations,
myeloid tumor-suppressor genes act as dominant negative, or via
Submitted 15 December 2016; accepted 15 December 2016. Prepublished
online as Blood First Edition paper, 27 December 2016; DOI 10.1182/blood2016-12-756619.
BLOOD, 9 FEBRUARY 2017 x VOLUME 129, NUMBER 6
haploinsufficiency, or via complete homozygous loss, and contribute
to phenotypic variability, phenotypic shifts, and progression to more
aggressive myeloid neoplasms. In the second review, Rumi and
I examine the 2016 revision of the World Health Organization (WHO)
classification of classical MPNs, and then discuss the need for a deeper
integration of clinical features, morphology, immunophenotype,
and genetics for defining and managing MPNs. In the third review,
Vannucchi and Harrison describe current therapies for ET, PV, and
PMF, focusing on emerging aspects within this diverse field. In the
fourth review, Reiter and Gotlib examine the myeloid neoplasms
with eosinophilia, focusing on the myeloid/lymphoid neoplasms
with eosinophilia and rearrangement of PDGFRA, PDGFRB,
or FGFR1, or with PCM1-JAK2. Finally, Maxson and Tyner discuss
the genomics of CNL, a distinct MPN with a high prevalence of
mutations in the CSF3R gene. They also examine a related disorder,
atypical CML, which has higher genetic complexity, including a
high prevalence of somatic mutations in the SETBP1 gene.12
Collectively, these reviews summarize the last 15 years or so of work in
the field of MPNs and related myeloid neoplasms, and provide a perspective
for future studies. I hope that Blood readers find this review series of interest.
Mario Cazzola
Associate Editor, Blood
References
1. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood.
1951;6(4):372-375.
2. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of
Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008.
3. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health
Organization classification of myeloid neoplasms and acute leukemia. Blood.
2016;127(20):2391-2405.
4. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the
PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic
hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201-1214.
5. James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to
constitutive signalling causes polycythaemia vera. Nature. 2005;434(7037):
1144-1148.
6. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in
myeloproliferative disorders. N Engl J Med. 2005;352(17):1779-1790.
7. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine
kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid
metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387-397.
8. Baxter EJ, Scott LM, Campbell PJ, et al; Cancer Genome Project. Acquired
mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.
Lancet. 2005;365(9464):1054-1061.
9. Maxson JE, Gotlib J, Pollyea DA, et al. Oncogenic CSF3R mutations in chronic
neutrophilic leukemia and atypical CML. N Engl J Med. 2013;368(19):1781-1790.
10. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin
in myeloproliferative neoplasms. N Engl J Med. 2013;369(25):2379-2390.
11. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in
myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;
369(25):2391-2405.
12. Piazza R, Valletta S, Winkelmann N, et al. Recurrent SETBP1 mutations in
atypical chronic myeloid leukemia. Nat Genet. 2013;45(1):18-24.
© 2017 by The American Society of Hematology
659
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
2017 129: 659
doi:10.1182/blood-2016-12-756619 originally published
online December 27, 2016
Introduction to a review series on myeloproliferative neoplasms
Mario Cazzola
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