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166 Part II Cellular Basis of Hematology

JAK2
C
C
JAK2 is widely expressed and is involved in signaling by single chain
hormone receptors, the common β chain family, and certain
C members of the class II receptor cytokine family. JAK2 deficiency is
C 13
lethal at day 12.5 caused by failure of erythropoiesis, which
explains the lack of reports of individuals with germline loss-of-
function JAK2 mutations. Receptor stimulation by EPO induces
tyrosine phosphorylation of JAK2, which is required for EPO func-
–/–
tion. Defective responses of cells from JAK2 mice also reveal its
WSXWS- motif essential role in the signaling of IL-3, GM-CSF, IL-5, TPO, and
−/−
14
IFN-γ, but not IL-6 and IFN-α/β. Transfer of JAK2 fetal liver
−/−
cells into irradiated JAK3 recipients resulted in normal thymic
subsets, arguing that JAK2 is not essential for T cell development.
Multiple groups have identified acquired activating mutations in
JAK2 as the etiology for virtually all cases of polycythemia vera, and
Box 1 in a significant percentage of cases of essential thrombocythemia and
primary myelofibrosis. JAK2 mutations have also been described in
Box 2 other hematopoietic neoplasms. JAK2 inhibitors have shown efficacy
at least in decreasing spleen size and constitutional symptoms in
Y patients with myeloproliferative neoplasms irrespective of whether
Y they harbor a JAK2 mutation.
Y
JAK3
Y
Y In contrast to the ubiquitous expression of the other JAKs, JAK3 is
predominantly expressed in hematopoietic tissues. JAK3 selectively
Y associates with only the γc, which is a component of multiple cytokine
receptors. Accordingly, mutation of γc or JAK3 results in a SCID
disorder in man, characterized by a lack of T and NK cells, with
Fig. 16.3 CYTOKINE RECEPTOR SUPERFAMILY. The general structure preservation of B cells, hence the designation T B NK SCID. Mice
−
+
−
of cytokine receptor superfamily. In the extracellular cytokine receptor homozygous for JAK3 null mutation show severe defects in lymphoid
module, four conserved cysteine residues exist and are involved in disulfide cells. B cell precursors in bone marrow, thymocytes, and both T and
bonds. A WSXWS (Tre, Ser, any, Tre, Ser) motif that is essential for receptor B cells are drastically decreased, although these defects can improve
15
processing, ligand binding, and activation of the receptor is also located in as aging occurs. Peripheral lymph nodes, NK cells, dendritic epi-
16
the extracellular domain. In the intracellular portion, two short domains dermal T cells, and intestinal intraepithelial gamma delta T cells are
termed Box 1 and Box 2 are important for JAK binding. Tyrosine residues are absent in these mice. Normal numbers of bone marrow hematopoietic
present on the intracellular part to be phosphorylated upon receptor progenitor cells with a similar capability to generate myeloid and
activation.
erythroid colonies as wild-type mice indicates specific defects in
lymphoid progenitor cells. Thymus progenitors are severely deficient.
This phenotype is attributable to failure of IL-7 and IL-2 signaling,
Janus Kinases which explains the T-cell deficiency while the absence of natural killer
cell development has been attributed to the impairment in IL-15
JAK proteins are tyrosine kinases of approximately 1000 amino acids. signaling. There is an increased apoptotic rate in the lymphocytes
They have clear nonredundant in vivo functions defined by analysis generated in these mice, and this is consistent with the identified
of gene deletion in mice, and mutations of JAK3 or Tyk2 in humans function of JAK3 in regulating Bcl-2 and Bax.
that lead to primary immunodeficiency syndromes (severe combined Activation of JAK3 because of gain-of-function mutations is
immunodeficiency [SCID] and autosomal-recessive hyperimmu- found in human hematologic malignancies, including acute mega-
5
noglobulin E syndrome [AR-HIES], respectively). In addition, karyoblastic leukemia and cutaneous T-cell lymphoma.
somatic mutations of JAKs are seen in human neoplastic conditions. Given the essential role of JAK3 in cytokine signaling through γc
The following is a brief description of JAK functions in cytokine and given its limited tissue expression, inhibition of JAK3 activity
signaling. Fig. 16.5A depicts the general structure of the JAK has emerged as a promising strategy for immunosuppression in
proteins. autoimmune disorders and immune rejection.
JAK1 Tyk2

JAK1 is widely expressed and associates with the IFN receptors and Tyk2 was the first JAK family member identified that plays a role in
−/−
receptors that use gp130 or the γc. JAK1 mice have grossly normal cytokine signaling. Tyk2 was discovered as an essential component in
12
17
nonlymphoid organogenesis ; however, they die perinatally of a a screen for mutants in IFN-α signaling. Type I IFN receptors
poorly characterized defect that may be neurologic. It is believed require Tyk2 and JAK1, while IFN-γ signaling depends on the
that this morbid phenotype is caused by the failure of cytokine sig- combination of Tyk2 and JAK2. The combination of Tyk2 with
naling that promotes neuronal cell survival via gp130. Defective JAK2 is not only required for IFN-γ signaling but also for the dif-
cytokine signaling is observed with class II cytokine receptors (IFNs), ferentiation of IFN-γ-producing Th1 cells from naive Th cells.
−/−
IL-2, IL-6, and IL-7 families. JAK1 mice manifest a SCID pheno- Lymphocyte development and proliferation are not affected in Tyk2-
type, consistent with the fact that JAK1 binds to the ligand-specific deficient mice, but signaling by cytokines that are important for host
receptor subunit of γc-. Somatic JAK1 activating mutations have defense is impaired. The IL-12 receptor (IL-12R) is associated with
been described in occasional cases of acute leukemia and solid Tyk2 and JAK2 and activates mainly the transcription factor STAT4.
tumors. IL-12 signaling is markedly impaired in the absence of Tyk2, and