2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Insights into the Molecular Genetics of
Myeloproliferative Neoplasms
By Huong (Marie) Nguyen, MD, and Jason Gotlib, MD, MS
Overview: The molecular biology of the BCR-ABL1-negative
chronic myeloproliferative neoplasms (MPNs) has witnessed
unprecedented advances since the discovery of the acquired
JAK2 V617F mutation in 2005. Despite the high prevalence of
JAK2 V617F in polycythemia vera (PV), essential thrombocythemia
(ET), and primary myelofibrosis (PMF), and the common
finding of dysregulated JAK-STAT signaling in these disorders,
it is now appreciated that MPN pathogenesis can reflect
the acquisition of multiple genetic mutations that alter several
biologic pathways, including epigenetic control of gene expression.
Although certain gene mutations are identified at
higher frequencies with disease evolution to the blast phase,
MPNS ARE clonal hematopoietic disorders that result
in overproduction of one or more terminally differentiated
blood cell types arising from the myeloid lineage. In
the 2008 World Health Organization (WHO) classification,
MPNs are divided into eight subtypes: chronic myeloid
leukemia (CML); polycythemia vera (PV); essential thrombocythemia
(ET); primary myelofibrosis (PMF); systemic
mastocytosis (SM); chronic neutrophilic leukemia; chronic
eosinophilic leukemia, not otherwise specified (CEL, NOS);
and MPN-unclassifiable (MPN-U). 1 Myeloid (and lymphoid)
neoplasms associated with eosinophilia and rearrangement
of platelet-derived growth factor receptor alpha or beta
(PDGFRA or PDGFRB) and fibroblast growth factor receptor1(FGFR1)
are distinguished by their own major WHO
disease category, but share numerous clinicopathologic features
with MPNs. 1 A pathogenetic hallmark of MPNs is
dysregulation of tyrosine kinases (TKs), which in turn results
in aberrant downstream signaling and increased cellular
proliferation and/or decreased apoptosis. Table 1
summarizes the molecular lesions (e.g., reciprocal chromosomal
translocations, point mutations, interstitial chromosomal
deletions) that generate oncogenic TKs in MPNs and
myeloid neoplasms associated with eosinophilia. The notion
that PV, ET, or MF is driven by a single TK lesion such as
JAK2 V617F has now been abandoned given the genetic and
epigenetic complexity observed in most patients (Fig. 1). The
cytogenetics of MPNs is important to understand disease
pathogenesis and prognosis; however, this topic is not addressed
in this monograph, and readers are directed elsewhere
for reviews on the subject.
Before JAK2 V617F: Clonality, Cytokine Independence,
and Aberrant JAK-STAT Signaling
In a 1951 Blood editorial, Dr. William Dameshek first
conceptualized the inter-relatedness of PV, ET, and MF and
postulated a “hitherto undiscovered stimulus” as the biologic
basis of their shared myeloproliferative features. 2 In the
1970s, Adamson and colleagues used restriction fragment
length polymorphism analysis of the X-linked glucose-6phosphate
dehydrogenase (G6PD) gene in a female patient
to confirm the clonal basis of PV, with ensuing studies
demonstrating clonality in ET and MF. 3 These investigations
were followed by two seminal observations: 1) hematopoietic
progenitors from patients with PV (and in some
MPN initiation and progression are not explained by a single,
temporal pattern of clonal changes. A complex interplay
between acquired molecular abnormalities and host genetic
background, in addition to the type and allelic burden of
mutations, contributes to the phenotypic heterogeneity of
MPNs. At the population level, an inherited predisposition to
developing MPNs is linked to a relatively common JAK2associated
haplotype (referred to as ‘46/1’), but it exhibits a
relatively low penetrance. This review details the current state
of knowledge of the molecular genetics of the classic MPNs
PV, ET, and PMF and discusses the clinical implications of
these findings.
cases ET and MF) proliferate in the absence of exogenous
cytokines such as erythropoietin (Epo) (e.g., endogenous
erythroid colony growth [EEC]), and 2) such cells are hypersensitive
to growth factors such as Epo, thrombopoietin
(Tpo), and interleukin-3 (IL-3). 4
The endogenous, self-stimulatory property of MPN cells
and cytokine hypersensitivity led to increasing interest in
JAK2 as a contributor to MPN pathogenesis. JAK2 belongs
to a family of four janus kinases, which also includes JAK1,
JAK3, and TYK2. Each JAK protein has an active tyrosine
kinase domain (JAK homology 1[JH1]), an inactive pseudokinase
domain (JAK homology 2 [JH2]), an SRC homology 2
domain (SH2), and an amino terminal FERM (4-point-1,
Erzin, Radixin, Moesin) homology domain, which binds to
the cytoplasmic tail of cytokine receptors. JAK2 facilitates
normal myelopoiesis by transmitting signals from type I
receptors for Epo (EpoR), thrombopoietin (TpoR or MPL),
granulocyte-colony-stimulating factor (G-CSFR), and IL-3
(IL-3R). In the normal state, binding of ligand to receptor
causes JAK2 to change from a receptor-bound, inactive
conformation to an active catalytic enzyme because of escape
from the inhibitory effects of the pseudokinase domain on
the kinase domain. 5 Auto-phosphorylation of JAK2 and
phosphorylation of downstream signaling intermediates results
in recruitment of SH2-domain containing proteins
such as STAT3 and STAT5. After phosphorylation by JAK2,
the STAT proteins homodimerize and translocate to the
nucleus, where they activate transcription of target genes
involved in regulating a variety of cellular processes, including
proliferation, differentiation, and apoptosis. Dampening
of JAK-STAT activation occurs via different negative feedback
mechanisms, including the suppressor of cytokine
signaling (SOCS) family of proteins, LNK, CBL, and various
tyrosine phosphatases.
From the Division of Hematology, Department of Medicine, Stanford University School of
Medicine/Stanford Cancer Institute, Stanford, CA.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Jason Gotlib, MD, MS, Associate Professor of Medicine,
Stanford Cancer Institute, 875 Blake Wilbur Drive, Room 2324, Stanford, CA 94305-5821;
email: jason.gotlib@stanford.edu.
© 2012 by American Society of Clinical Oncology.
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