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Chapter 68 The Polycythemias 1075

morbidity is not corrected by maintaining a normal hematocrit. to dysregulated EPOR expression, hypersensitivity to EPO stimula-
Characteristic laboratory findings are (1) an increased hematocrit and tion, and heightened JAK–STAT activation. Expression of truncated
RBC mass without an increased leukocyte or platelet count, (2) an EPOR in murine B-cell progenitors leads to the development of ALL
absence of an activating mutation of JAK2, (3) a normal hemoglobin– in vivo (see Chapters 64 and 66). Several observations suggest that the
oxygen dissociation curve, (4) low serum EPO levels, and (5) in vitro EPOR mutations in human leukemic cells in Ph-like ALL are driver
hypersensitivity of erythroid progenitors to EPO. Even though PFCP mutations that are acquired during early stages of leukemogenesis
is present at birth, many affected patients are incidentally diagnosed and are logical targets for therapeutic targeting with JAK2 inhibitors.
later in life after the performance of routine blood counts or when Mutations of genes encoding proteins other than the EPOR
evaluated in the context of multiple family members having polycy- account for most cases of PFCP. Mutations of the EPOR have been
themia. It is of interest that one individual so affected was an found in only 10–20% of subjects with PFCP. Additional disease-
accomplished cross-country skier who had won medals at the Olympic causing genes and their mutations have yet to be identified. In
Games. Numerous mutations of the EPOR associated with PFCP patients with erythrocytosis who are JAK2V617F negative and do not
have been described, leading to a loss in the negative regulatory have a JAK2 exon 12 mutation, and who have life-long erythrocytosis
domain of the EPOR. associated with a low serum EPO level, sequencing of the EPOR
The physiologic basis for EPO-mediated activation of erythropoi- should be pursued.
esis is as follows: EPO activates its receptor by conformational
changes of its dimers, leading to initiation of an erythroid-specific
cascade of events. The first signal is initiated by the binding of a SECONDARY POLYCYTHEMIAS
tyrosine kinase to the EPOR and its phosphorylation and activation
of a transcription factor, STAT5, which regulates erythroid-specific Secondary polycythemias can be either congenital or acquired (see
genes. This “on” signal is negated by dephosphorylation of the EPOR Table 68.1). Conditions leading to hypoxia, such as high altitude, cya-
by HCP, that is, the “off” signal. Truncation of the EPOR leads to a notic heart disease, or chronic lung disease, may result in physiologic
loss in the negative regulatory domain of the EPOR, a binding site polycythemia mediated by increased levels of EPO. There are marked
for HCP, leading to a gain-of-function mutation of the EPOR (see variations in EPO levels and subsequent erythroid response in the
Fig. 68.2). In addition, the negative regulation of erythropoiesis by face of chronic hypoxia, suggesting that some of these factors may be
SOCS-3, cytokine-inducible SH2 domain containing protein (CIS), genetically determined. The same degree of renal tissue hypoxia may
and Src homology region 2 domain-containing phosphatase-1 induce substantially different levels of EPO production in response
(SHP-1) is presumed to contribute to the underlying cause of PFCP. to high altitude. It is likely that these individual variations are a
Alternative explanations for the increased sensitivity of erythroid function of genetic differences in hypoxia sensing and the hypoxia
progenitors to EPO of patients with PFCP have been proposed. response pathways. For purposes of simplicity and clinical diagnostic
EPOR downregulation provides another mechanism by which EPO usefulness, the secondary polycythemic disorders are divided into
desensitization can occur. EPOR downregulation is a complex process those that are acquired and those that are congenital. It should
that involves EPOR-induced internalization or ubiquitination and be kept in mind that this division, although useful for differential
degradation by proteasomes. EPO-induced receptor internalization diagnosis, is artificial. Patients with inherited germ-line mutations,
is an efficient means of rapidly reducing EPO responsiveness. This for instance, can develop an EPO-secreting pheochromocytoma
process is mediated by binding of the EPOR to the p85 subunit of or renal cell cancer, and a patient with PV can smoke and have
phosphatidylinositol 3-kinase (PI3K) but does not involve its kinase chronic obstructive pulmonary disease (COPD). In other instances,
activity as the PI3K inhibitor wortmannin does not impair EPOR polycythemia caused by a germ-line mutation can be masked by an
internalization. All of the truncated mutants associated with PFCP acquired environmental factor or another gene-modifying mutation.
are associated with failure to internalize the EPOR, contributing to
prolonged signaling through the EPOR. The EPOR degradation Acquired Secondary Polycythemias
process removes all of the phosphorylated tyrosine residues in the
intracellular domain of the receptor, thereby preventing further signal
transduction. The remaining part of the EPO–EPOR complex is Polycythemias of Cyanotic Heart Disease and
then internalized and degraded by lysosomes. The E3 ligase Pulmonary Disease
B-transducin repeat containing protein-1 (B-Trcp-1) is responsible
for EPOR ubiquitination and degradation. Mutations in B-Trcp-1 Patients with cyanotic heart disease and pulmonary disease frequently
abolish EPOR ubiquitination and degradation, making cells express- have arterial hypoxemia, leading to increased production of EPO and
ing the EPORs hypersensitive to EPO. Each of the PFCP mutations polycythemia. Excessive EPO production occurs when the PaO 2 is
involving the EPOR results in loss of the binding site for B-Trcp-1. sustained below 67 mmHg as a result of severely impaired pulmonary
These findings suggest that the EPO hypersensitivity in PFCP might mechanics. Because patients with severe pulmonary disease and sec-
not only be attributable to a failure to recruit negative regulators such ondary erythrocytosis frequently have elevated plasma volumes, the
as phosphatases to inactivate JAK2, but that these mutant receptors degree of elevation of the hematocrit level may be modest. Hematocrit
are defective in EPO-induced receptor downregulation. levels as high as 65% or rarely 75% have, however, been reported.
The effect of a truncated EPOR is not always predictable. Some Moderate elevations of hematocrit have been estimated to occur in
patients who inherit an EPOR mutation are not polycythemic. This 20% of patients with COPD. Polycythemia in this setting can con-
observation suggests that undefined environmental or genetic factors tribute to pulmonary hypertension, pulmonary endothelial cell dys-
may mask the development of polycythemia. Also, the heterogeneity function, reduced cerebral blood flow, hyperuricemia, gout, and an
of the polycythemic phenotype observed in a PFCP animal model increased risk of venous thromboembolic disease.
appears to be strain dependent. This indicates that gene modifiers Why some patients with pulmonary disease and congenital heart
or epigenetic factors may mask the development of the full PFCP disease develop polycythemia but others do not is not clear. Increased
phenotype. Recently, four different rearrangements of the EPOR oxygen-carrying capacity may improve oxygen delivery; however, it
have been observed in Philadelphia chromosome-like (Ph-like) is not obvious at what hematocrit level the resultant elevation in
acute lymphoblastic leukemia (ALL) B cells. Normal B cells do not blood viscosity impairs blood flow to the tissues, leading to a reduc-
express the EPOR, but the EPOR has been described in ETV6- tion in oxygen uptake. In addition, oxygen uptake to the tissues is
RUNX1–positive ALL blast cells. All of these rearrangements are markedly influenced by whole blood volume. Thus, whereas the
different from those observed in PFCP but result in truncation of optimal hematocrit level for oxygen delivery is about 45% in normo-
the cytoplasmic tail of the EPOR at residues similar to those mutated volemic subjects, it rises to over 60% in hypervolemic states, likely
in PFCP, with preservation of the proximal tyrosine essential for as a result of engorgement of the vascular bed and a decrease in
receptor activation and loss of distal regulatory residues. This leads peripheral resistance. Furthermore, chronic exposure to hypoxia leads