JAK: Not Just Another Kinase

Abstract

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) axis is implicated in cancer, inflammation, and immunity. Numerous cytokines/growth factors affect JAK/STAT signaling. JAKs (JAK1, JAK2, JAK3, and TYK2) noncovalently associate with cytokine receptors, mediate receptor tyrosine phosphorylation, and recruit ≥1 STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). Tyrosine-phosphorylated STATs dimerize and are then transported into the nucleus to function as transcription factors. Signaling is attenuated by specific suppressor of cytokine signaling (SOCS) proteins, creating a negative feedback loop. Both germline mutations and polymorphisms of JAK family members correlate with specific diseases: systemic lupus erythematosus (TYK2 polymorphisms); severe combined immunodeficiency (JAK3 mutations); pediatric acute lymphoblastic leukemia (TYK2 mutations); and hereditary thrombocytosis (JAK2 mutations). Somatic gain-of-function JAK mutations mainly occur in hematologic malignancies, with the activating JAK2 V617F being a myeloproliferative disorder hallmark; it is also seen in clonal hematopoiesis of indeterminate potential. Several T-cell malignancies, as well as B-cell acute lymphoblastic leukemia, and acute megakaryoblastic leukemia also harbor JAK family somatic alterations. On the other hand, JAK2 copy number loss is associated with immune checkpoint inhibitor resistance. JAK inhibitors (jakinibs) have been deployed in many conditions with JAK activation; they are approved in myeloproliferative disorders, rheumatoid and psoriatic arthritis, atopic dermatitis, ulcerative colitis, graft-versus-host disease, alopecia areata, ankylosing spondylitis, and in patients hospitalized for COVID-19. Clinical trials are investigating jakinibs in multiple other autoimmune/inflammatory conditions. Furthermore, dermatologic and neurologic improvement has been observed in children with Aicardi-Goutieres syndrome (a genetic interferonopathy) treated with JAK inhibitors.

Introduction

Janus kinase or “just another kinase” (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-signal transducers and activators of transcription (JAK-STAT) pathway (1,2). The name Janus originates from the two-faced Roman god of duality, because JAKs possess two similar phosphate-transferring domains, one of which displays the kinase enzymatic activity, while the other motif negatively regulates the kinase activity of the first in a feedback loop (1).

JAK-STAT signaling is composed of three major proteins: cell-surface receptors, JAKs, and STATs. JAKs function as tyrosine kinase enzymes that are bound to the cytoplasmic regions of type I and II cytokine receptors. Once a ligand binds to the receptor, JAKs add phosphates to the receptor. Two STAT proteins then bind to the phosphates and form a dimer. The dimer enters the nucleus, binds to DNA, and transcription of target genes ensues. Overall, the JAK-STAT pathway is vital for the proliferation and survival of cancer cells and may contribute to drug resistance (2).

The JAK-STAT pathway is activated by over 50 different pro-cytokine receptors that control hematopoiesis, the immune response, embryogenesis, and inflammation through the signaling pathway (3,4,5,6). This pathway has an important role in the pathogenesis of a variety of immune-mediated diseases and malignant processes.

JAK inhibitors are a class of medications that function to block signaling through the JAK-STAT pathway (3). JAK inhibitors (also called jakinibs) function by preventing the JAK protein from phosphorylating, therefore attenuating intracellular signaling. The most extensive clinical studies for JAK inhibitors have been in rheumatoid arthritis (RA) and myelofibrosis (MF), but JAK inhibitors have also been applied in dermatology for treatment of conditions such as psoriasis/psoriatic arthritis, atopic dermatitis, alopecia areata, vitiligo, and dermatomyositis (5–22).

JAK: Structure and function

Over 50 cytokines signal via the JAK/STAT pathway to orchestrate hematopoiesis, regulate immunity, and induce inflammation. The main function of the JAK-STAT pathway is to transfer signals from the receptors on the cell membrane, which can be categorized as including interleukin (IL) receptors, interferon (IFN) receptors, or colony stimulating factor receptors (CSFRs), to the nucleus. The pathway is necessary for cytokines and growth factor function, leading to essential cellular processes such as myeloid and lymphoid differentiation/proliferation/hematopoiesis, lactation, development of the immune system, and proinflammatory response (Figure 1) (23–28).

Figure 1: Functional Roles of JAK1, JAK2, JAK3, TYK2/STAT Pathways:

There are several members of the JAK family and the TYK protein that are involved in the JAK/STAT pathway. Some examples are shown. Important roles of these pathways include enhanced regulatory response and immune system regulation, myeloid and lymphoid differentiation/proliferation, and proinflammatory response (25–27)

Abbreviations: IFN- interferon; IL- interleukin; JAK- Janus kinase; STAT- signal transducer and activator of transcription; TYK- tyrosine kinase

Cytokines are secreted glycoproteins that operate as intercellular messengers, stimulating differentiation, proliferation, and programmed cell death of their target cells. They act by binding to specific receptors on the target cell surface and switching on a phosphotyrosine-based intracellular signaling cascade initiated by kinase enzymes and then propagated by SH2 domain-containing transcription factors. As cytokine signaling is proliferative and often inflammatory, it’s amplitude and duration is tightly controlled.

Most cytokines are small helical-bundle proteins, generally 150–200 amino acids in length (4). They are divided into two classes based on elements discerned in their receptors. Class I cytokines consist of four α-helices in an up-up-down-down configuration. Some of these, such as IL-5, exist as dimers, but the topology is conserved. The up-up-down-down conformation requires two long loops to connect the up-up and down-down pairs. In class II cytokines, one or both of these loops is replaced by an extra α-helix resulting in five to six helices arranged in an anti-parallel manner.

Class I cytokines signaling through JAK-STAT include, but are not limited to IL-2, IL-3 family, IL-4, IL-6 family, IL-7, IL-9, IL-12, IL-13, IL-15, IL-21, IL-23, G-CSF, GM-CSF, EPO, TPO (4). Class II cytokines include, but are not limited to interferon-alpha, -beta, -epsilon, -kappa, -omega, -gamma, IL-10, IL-19, IL-20, IL-22, IL-24, IL-26 (4).

The cytokine signaling cascade needs only three elements (receptor, kinase, and transcription factor) to elicit a response. Each cytokine binds to a specific receptor on its target cell surface. These receptors contain intracellular motifs that are constitutively associated with members of the JAK family of tyrosine kinase enzymes. The four JAK family members are: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). JAKs are inactive prior to cytokine exposure. However, once the cytokine binds to its receptor, it induces their auto-activation by transphosphorylation. Once activated, JAKs phosphorylate the intracellular tails of the receptors on specific tyrosines, which in turn act as docking sites for member of the STAT family of transcription factors. The STAT family is composed of seven members STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6, which mainly act, as mentioned, as transcription factors. Receptor-localized STATs are then phosphorylated by JAK, which leads to their disassociation from the receptor and translocation to the nucleus, where they drive the expression of cytokine-responsive genes. To guarantee that signaling is properly switched off, a number of proteins act to dampen cytokine signaling at numerous levels of the pathway. Importantly, the suppressors of cytokine signaling (SOCS) family are negative feedback inhibitors of the signaling cascade. A general rule of cytokine signaling is that each cytokine binds to a specific receptor, which promotes activation of specific JAK(s) and STAT(s), and signaling is switched off by a specific SOCS protein.

Germline JAK family mutations

JAK family members--JAK1, JAK2, JAK3, and TYK2---are implicated in cell growth, survival, and development, and are critically important for differentiation of a variety of cells including immune cells and hematopoietic elements. Therefore, it is not surprising that germline mutations or specific polymorphisms in these genes are associated with disease. A striking phenotype associated with inactivating JAK3 germline mutations is severe combined immunodeficiency syndrome (Table 1) (29–36). JAK3 missense mutations have also been found in patients with clear cell renal cell cancer. Pediatric acute lymphoblastic leukemia has been associated anecdotally with germline TYK2 mutations, and hereditary thrombocytosis with JAK2 germline mutations. Finally, the autoimmune disease systemic lupus erythematosus has been linked to TYK2 polymorphisms.

Table 1:

Examples of Diseases Associated with Germline JAK Mutations or Polymorphisms

Mutation	Syndrome	Features	Frequency and inheritance	References
JAK3	Severe combined immunodeficiency disorder	Lack of T and NK cells, impaired B-cell function, severe and recurrent opportunistic infections Loss of functional JAK3 protein results in the absence of T cells and natural killer cells and a normal number of poorly functioning B cells	7–14% due to germline JAK3 mutations Autosomal recessive	(29)
JAK3	Clear cell renal cell cancer	Patients with JAK3 mutations more frequently presented with metastases (3 out of 4 [75%] vs. 4 out of 46 [9%]; P = 0.004) and had poorer survival (P = 0.049)	Four different JAK3 germline missense mutations (p.Gln13Lys; p.Arg925Ser; p.Ala677Thr, p.Val722Ile) were found in a total of 7 patients (14%), but in none of the controls (P = 0.0006). Note: The cohort was small and the data has not been replicated	(30)
TYK2	Pediatric acute lymphoblastic leukemia (ALL).	Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition	Anecdotal For instance, in two patients, germline mutations in TYK2, were located in two adjacent codons of the pseudokinase domain (p.Pro760Leu and p.Gly761Val).	(31)
JAK2	Hereditary thrombocytosis	Familial myeloproliferative disorder with clinical features resembling sporadic essential thrombocythemia.	JAK2 germline mutation In some families, germline mutations have been identified in the genes for thrombopoietin and its receptor, MPL.	(32, 33)
JAK2	Myeloproliferative neoplasms	Familial myeloproliferative	Germline JAK2 mutations causing familial myeloproliferative neoplasms have been reported and also specific constitutional JAK2 haplotype (46/1) was associated with the predisposition to myeloproliferative neoplasms with somatic JAK2 V617F mutations	(34,35)
TYK2	Systemic lupus erythematosus (SLE)	Autoimmune disease	TYK2 and IFN regulatory factor 5 (IRF5) genes showed polymorphisms linked with SLE TYK2 binds to the type I IFN receptor complex and IRF5 is a regulator of type I IFN gene expression	(36)

Diseases associated with somatic JAK family mutations

Both activating and loss-of-function somatic alterations in JAK genes can occur. Activating JAK alterations are associated with development of mostly hematologic malignancies. Loss-of function JAK2 alterations are associated with immune checkpoint blockade resistance (37–57).

JAK activating alterations:

Somatic alterations in various JAK genes are predominantly associated with a variety of hematologic malignancies (Table 2) (37–57). As an example, the acquired somatic mutation JAK2 V617F, which constitutively activates JAK2 kinase, is the most frequent molecular event in myeloproliferative disorders. It is observed in about 95% of cases of polycythemia vera and in 55–60% cases of essential thrombocytosis and primary myelofibrosis. JAK2 V617F is also found in the normal population. Among 49,488 individuals from the Copenhagen General Population Study, 63 (0.1%) tested positive for the JAK2V617F mutation. Of these, 48 were eventually diagnosed with a myeloproliferative neoplasm (49). JAK2 V617F mutations in healthy people are referred to as clonal hematopoiesis of indeterminate potential (CHIP), which defines the presence of a clonally expanded hematopoietic stem cell caused by a leukemogenic mutation in individuals without evidence of dysplasia, cytopenia or hematologic malignancy. CHIP correlates with a 0.5–1.0% risk per year of leukemia. Importantly, CHIP also confers a two-fold increase in cardiovascular risk independent of conventional risk factors and is also associated with venous thromboembolism and other inflammatory states. Other CHIP mutations (in addition to JAK2 V617F) occur in DNA damage repair genes PPM1D and TP53, epigenetic regulators ASXL1, DNMT3A, TET2, and mRNA spliceosome components SF3B1, and SRSF2, as well as other genes (50). Interestingly, patients with Erdheim Chester Disease, a non-Langerhans histiocytosis, appear to have elevated rates of myeloproliferative disorders, sometimes heralded by a JAK2 V617F mutation (51). JAK family mutations are also observed in a subset of patients with a variety of T-cell malignancies, including T-ALL, T-PLL and Sezary syndrome, as well as childhood B-cell precursory ALL, and acute megakaryoblastic leukemia (with and without Down syndrome (37–48). An activating JAK1 mutation has been reported in Castleman’s disease as well and may explain an exceptional response to the anti-IL6 antibody siltuximab in the reported patient in the absence of elevated IL6 levels, since the JAK1 mutation may have sensitized the receptor to the IL6 ligand (42). Finally, a TEL-JAK2 fusion protein that includes the catalytic domain of JAK2 and the TEL-specific oligomerization domain, resulting in constitutive activation of its tyrosine kinase activity, has been seen in ALL and in atypical chronic myelogenous leukemia (44).

Table 2:

Examples of Diseases Associated with Somatic JAK family Mutations (37–57)

Disease	Mutations and Frequency	References
T-ALL	Constitutive activation of JAK-STAT signaling seen in one-third of T-ALL; caused by activating mutations IL7R, JAK1 or JAK3, or in STAT5B A t(9;12)(p24;p13) chromosomal translocation in a T-cell childhood ALL patient fused the 3’ portion of JAK2 to the 5’ region of TEL, a gene encoding a member of the ETS transcription factor family. The TEL-JAK2 protein included the JAK2 catalytic domain and the TEL-specific oligomerization domain, resulting in constitutive tyrosine kinase activity Also seen in atypical chronic myelogenous leukemia	(37) (44)
Childhood B-cell precursor ALL	JAK2 mutations in 3.5% of cases	(38)
B-ALL	JAK2 mutations are frequent in the specific subtype of B-ALL (“Ph-like”) and JAK2 fusion genes with various partner genes, such as ETV6-JAK2, were also found in this type of B-ALL.	(39)
BCR-ABL1-negative, high-risk pediatric ALL	Activating JAK1, JAK2 and JAK3 mutations in 10.7% BCR-ABL1-negative, high-risk pediatric ALL cases.	(40)
Myeloproliferative disorders	JAK2 V617F mutation is considered the most important criterion in the diagnosis of Bcr-Abl-negative neoplasms and is thus used as a clonal marker. Seen in 95% in polycythemia vera; 55–60% in essential thrombocytosis and primary myelofibrosis.	(41)
Castleman disease	Anecdotal case of JAK1 mutation Patient had exceptional response to siltuximab (anti-IL-6) without evidence of increased blood levels of IL-6, perhaps because JAK1 mutation sensitized JAK-STAT signaling to IL-6	(42)
Sezary syndrome (T-cell lymphoma type)	Gain-of-function mutations in JAK1, JAK3, STAT3 and STAT5B (JAK/STAT total ∼11% of patients).	(43)
Acute megakaryoblastic leukemia	Activating mutations of the JAK3 gene in both Down syndrome and non-Down syndrome-associated acute megakaryoblastic leukemia. These mutations include A572V and V722I substitutions in the JH2 pseudokinase domain, and a P132T substitution in the JH6 part of the receptor-binding domain.	(45–47)
T-cell prolymphocytic leukemia (T-PLL)	Overall, 62.1% of cases harbored mutated JAK or STAT genes. Most frequently, JAK1 (6.3%), JAK3 (36.4%), and STAT5B (18.8%) carried somatic single-nucleotide variants, with missense mutations in the SH2 or pseudokinase domains being most common. Importantly, these lesions were predominantly subclonal.	(48)
Loss- or gain-of-function JAK alterations
Resistance to immune checkpoint blockade	JAK2 deletions (often accompanied by deletions in PDL1) (on the same amplicon)	(52–55)
Sensitivity to immune checkpoint blockade	JAK2 amplifications may accompany PDL1 amplification (on the same amplicon	(56,57)

Abbreviations: ALL = acute lymphoblastic leukemia; T-ALL = T cell acute lymphoblastic leukemia

JAK loss-of-function alterations:

Somatic genomic copy number alterations, involving loss of the key interferon-γ gene function inducer JAK2, are a pivotal driver of immune resistance and escape. Acquired resistance to immune checkpoint therapy, including PD-1 blockade, in patients with advanced melanoma and other cancers has been associated with JAK2 deletion and loss-of-function mutations, respectively (52–55). In depth study showed that the deletion of JAK2 and PD-LI, two neighboring genes found on chromosome 9p24, was associated with primary resistance to anti-PD-1 immunotherapy in recurrent human papilloma virus-negative head and neck squamous cancers (54). The latter findings regarding resistance to immune checkpoint blockade were confirmed (55), and CAP/CLIA validated for use in the clinic to select optimal therapy in this setting. Therefore, lack of JAK2-mediated interferon-γ responsiveness allows cancer cells to escape from antitumor T cells and, in the context of anti-PD-1/L1 immunotherapy, abrogates the antitumor efficacy of this approach. Consistent with these PD-L1-JAK2 co-deletion resistance findings, JAK2, PD-L1 (and PDL2) (9p24.1) amplification, or 9p copy number gain, have been associated with opposite effects, namely anti–PD-1 immunotherapy benefit. Increased PD-L1 expression, which can be directly caused by 9p24.1 amplification (or 9p copy number gain) and indirectly caused by increased JAK2 signaling, has been associated with immunotherapy response against tumors with 9p amplification (56,57). These results may apply to other tumors/sites and therapies, especially given the pivotal, broad role of JAK2 in cancer cell sensitivity to IFN-γ, impaired antigen presentation, T cell sensitivity, and evasion.

JAK inhibitors in the clinic

A wealth of functional data provided strong motivation for the generation of inhibitors that block the enzymatic activity of JAK as a new type of immunomodulatory medication. Preclinical disease models, including in arthritis, transplantation, graft-versus-host disease and other autoimmune conditions led to clinical trials. Moreover, the discovery of gain-of-function mutations of JAK2 in myeloproliferative neoplasms, including myelofibrosis, polycythemia vera and essential thrombocytosis, provided additional impetus for developing JAK inhibitors (jakinibs) for the clinic (Table 3) (58–67).

Table 3:

Examples of JAK inhibitors approved by the FDA in the clinic (58–67)

Drug	JAKs inhibited with IC50 <150 nM*	Approval indication	References
Abrocitinib	JAK1 = 29 nM	Atopic dermatitis (Significant improvements vs placebo (≥75% improvement in lesion extent and severity) were shown for patients with moderate to severe topic dermatitis (generally over 40 to 50% at 200 mg doses)	(66)
Baricitinib	JAK1 = 5.9 nM JAK2 = 5.7 nM	Rheumatoid arthritis, alopecia areata Rheumatoid arthritis More patients who received baricitinib than those who received placebo achieved ACR20, ACR50, and ACR70 responses at week 12 and week 24 (ACR response is scored as a percentage improvement, comparing disease activity at two discrete time points (usually baseline and post-baseline comparison)). Alopecia areata: 17% to 35% of patients showed improvement The FDA issued an Emergency Use Authorization for baricitinib in combination with remdesivir, and subsequently alone, for the treatment of suspected or laboratory confirmed COVID-19 in hospitalized patients	(62,63)
Fedratinib	JAK2 = 3 nM	Myelofibrosis (~40% responders)	(64)
Ruxolitinib	JAK1 = 3.3 nM JAK2 = 2.8 nM	Myelofibrosis (~50% of patients are responders) Polycythemia vera (~20% are responders) Graft-versus-host disease (~70% are responders) Topical cream for atopic dermatitis (~50% are responders)	(60,61, 67)
Tofacitinib	JAK1 = 112nM, JAK2 = 20 nM JAK3 = 1 nM	Rheumatoid arthritis (~60% are responders) Psoriatic arthritis (~30 to 50% are responders) Ulcerative colitis (~20% remission by week 8) Polyarticular juvenile idiopathic arthritis (At week 44, the tofacitinib-treated patients who achieved a response at the end of the study’s first phase had a statistically significant lower occurrence of disease flare (31%) than placebo-treated patients (55%; P=0.0007)).	(58,59)
Upadacitinib	JAK1 = 45 nM JAK2 = 109 nM	Rheumatoid arthritis (~50% are responders) Psoriatic arthritis (~35% are responders) Atopic dermatitis (>50% are responders) Ankylosing spondylitis (~50%are responders)	(65)

^*Information from: JAK Inhibition | JAK Inhibitor Review (selleckchem.com)

Abbreviations: IC50= half-maximal inhibitory concentration

The first JAK inhibitor to receive approval was the JAK1/JAK2 inhibitor ruxolitinib (50,61,67). Based on the identification of gain-of-function JAK2 mutations in myelofibrosis, ruxolitinib was approved in 2011 for this indication. Subsequently, ruxolitinib has also been approved for steroid-refractory acute graft-versus-host disease, and a cream form for atopic dermatitis. More recently, fedratinib, a selective JAK2 inhibitor, was also approved for myelofibrosis (64).

Tofacitinib, a JAK1/JAK2/JAK3 inhibitor, is approved for rheumatoid arthritis, psoriatic arthritis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis (57,58). Baricitinib is a JAK1/JAK2 inhibitor approved for rheumatoid arthritis and more recently for alopecia areata. It is also approved for the treatment of atopic dermatitis (AD) in Europe and has recently received emergency FDA approval, with and without the antiviral remdesivir, for the treatment of COVID-19 in hospitalized patients (62,63). Upadacitinib has a degree of selectivity for JAK1 over JAK2 and is approved for the treatment of rheumatoid arthritis, psoriatic arthritis and atopic dermatitis (63). Abrocitinb is also a selective JAK1 inhibitor approved for atopic dermatitis (64). Several other JAK inhibitors have been authorized for similar indications in Europe or Japan: filgotinib, peficitinib, delgocitinib, and oclacitinib (66).

Ongoing clinical trials are investigating the efficacy of jakinibs in a wide variety of additional conditions such as alopecia areata, ankylosing spondylitis, inflammatory bowel disease, dermatomyositis, interstitial lung disease, lupus, vasculitides, vitiligo and myasthenia gravis. Finally, recent results suggest improvement in dermatologic abnormalities and in neurologic function in children with Aicardi-Goutieres syndrome (a genetic interferonopathy associated with severe disability and death) (68).

JAK inhibitors carry an increased risk of infection as a side effect. The incidence of common infections such as upper respiratory tract, lower respiratory tract (including tuberculosis), and urinary tract infections are higher compared with the general population (69). In addition, for those JAK inhibitors used to treat chronic inflammatory conditions, the FDA requires warning about increased risk of cardiac events, cancer, and blood clots (70,71).

Interaction of JAK/STAT with cross talking signaling pathways: Implications for future therapeutic interventions

Different components of the JAK/STAT pathway, such as receptors, JAK, STAT, and gene transcription factors cross talk with other signaling pathways. These signaling cross talks play very important roles in pluripotency, differentiation, immune regulation, and tumorigenesis, which may be important for future therapeutic developments (72,73). Specifically, components of the transforming growth factor-β (TGFβ) signaling pathway, which is involved in embryonic development and cell homeostasis, interact with components in the JAK/STAT pathway, and can either upregulate or downregulate the pathway (72,73). SMAD proteins, the modulators of the TGFβ pathway, and STAT proteins often share the same transcription complex. One example is the STAT3 and SMAD1 complex linked by p300, which induces astrocyte differentiation.

The TGFβ signaling pathway is modulated by the Notch pathway, which is involved in cell proliferation, differentiation, and cell death (72, 73). Components of the Notch pathway also cross talk with the JAK/STAT pathway and have been studied in organ development in Drosophila. The Notch pathway suppresses JAK/STAT signals through interference of STAT translocation to the DNA domain (72). For example, in the development of the Drosophila central nervous system, Hes proteins (downstream effectors of Notch) facilitate JAK2 phosphorylation of STAT3 (72, 73).

The cross talk between these pathways suggests that TGFβ and Notch pathway modulators may deserve consideration in the future when developing JAK pathway inhibitors.

Conclusions

Janus kinase or “just another kinase” (JAK) is a family of intracellular, non-receptor tyrosine kinase enzymes that convert cytokine-mediated signals via the JAK- STAT pathway into nuclear effects. Over 50 cytokines signal via the JAK/STAT pathway to coordinate hematopoiesis, immune function, and inflammation. The four JAK family members are: JAK1, JAK2, JAK3 and TYK2. The STAT family, which mainly act as transcription factors, is composed of seven members STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6. The cytokine signaling cascade requires only three elements (receptor, kinase, and transcription factor) to elicit a biologic impact. Each cytokine binds to a specific receptor, which promotes activation of specific JAK(s) and STAT(s); receptor-localized STATs are phosphorylated by JAK, which leads to their disassociation from the receptor and translocation to the nucleus, where they induce the expression of cytokine-responsive genes; signaling is switched off by a specific SOCS protein via a negative feedback loop.

JAK family members are associated with both germline mutations and polymorphisms that correlate with specific disease manifestations (Table 1) (29–36). The autoimmune disease systemic lupus erythematosus has been linked to TYK2 polymorphisms. JAK3 germline mutations have been seen in severe combined immunodeficiency syndrome and in clear cell renal cell cancer. Pediatric acute lymphoblastic leukemia has been associated with germline TYK2 mutations, and hereditary thrombocytosis with JAK2 germline mutations.

Somatic gain-of-function mutations in JAK genes are predominantly associated with hematologic malignancies (Table 2) (37–48). The somatic mutation JAK2 V617F, which constitutively activates JAK2 kinase, is a hallmark of myeloproliferative disorders including polycythemia vera, essential thrombocytosis and primary myelofibrosis. JAK2 V617F is also found in the normal population and increases with aging as part of a phenomenon known as clonal hematopoiesis of indeterminate potential, which enhances risk for development of leukemia as well as for cardiac events and thromboembolism. JAK family somatic mutations are also observed in a subset of patients with a variety of T-cell malignancies--T-ALL, T-PLL and Sezary syndrome--as well as in childhood B-cell precursory ALL, and acute megakaryoblastic leukemia (with and without Down syndrome,) and in Castleman’s disease. Finally, an activating TEL-JAK2 fusion protein has been reported in ALL and in atypical chronic myelogenous leukemia (42).

JAK2 copy number loss, resulting in abrogation of JAK2 function, is also important. In particular, JAK2 gene loss is a pivotal driver of immune resistance and escape in cancer, and is associated with resistance to immunotherapy.

Because JAK family gain-of-function aberrant proteins are implicated in a spectrum of illnesses, JAK inhibitors have been deployed to treat these conditions. JAK inhibitors or jakinibs are now approved for a variety of medical problems including, but not limited to myeloproliferative disorders (ruxolitinib and fedratinib), graft-versus-host disease (ruxolitinib), rheumatoid arthritis (tofacitinib, baricitinib, and upadacitinib), psoriatic arthritis (tofactitinib and upadacitinib) atopic dermatitis (abrocitinib, upadacitinib and topical ruxolitinib), ulcerative colitis (tofacitinib), ankylosing spondylitis (tofacitinib, upadacitinib), and COVID-19 in hospitalized patients (baricitinib) (Table 3) (58–67), as well as most recently, baricitinib for alopecia (74). Future research will elucidate the potential of jakinibs in numerous other autoimmune illnesses including, but not limited to alopecia areata, ankylosing spondylitis, inflammatory bowel disease, dermatomyositis, lupus, vasculitides, vitiligo and myasthenia gravis. Interestingly, recent observations suggest improvement in neurologic function and in skin abnormalities in children with Aicardi-Goutieres syndrome (a genetic interferonopathy resulting in severe disability and death). Interactions of JAK molecules with other signaling pathways such as TGF-β and notch may also need to be considered. Taken together, JAK inhibitors are transforming outcomes for many disorders, from cancer to autoimmunity and beyond.