Table 3 Role of different STATs in cancer and immune diseases

Inducible transcriptional activation

STAT1

Germline LoF mutation

Susceptibility to intracellular pathogens and herpetic infection, due to defective IFN responses

[99]

Germline GoF mutation

Mucocutaneous candidiasis, recurrent respiratory infection, cancer, autoimmune cytopenias, due enhanced responses to IFNs and other cytokines

[100]

STAT2

Germline LoF mutation

Susceptibility to viral disease, due to defective IFN responses

[101]

Germline GoF mutation

Various autoinflammatory disorders, due to enhanced IFN responses

[100]

STAT3

Germline LoF mutation

Hyper-IgE syndrome, with cutaneous and respiratory infections and skeletal abnormalities, due to defective signaling by multiple IL-6-related cytokines

[99]

Germline GoF mutation

Multiorgan autoimmunity, short stature, lymphoproliferation, due to enhanced signaling by IL-6 and related cytokines

[100]

Acquired activating mutation

Large granular lymphocytic (LGL) leukemia and diffuse large B cell leukemia (DLBCL), due to augmented proliferation and survival

[102]

Hyperactivation due to upstream components

Various cancers, such as head and neck squamous cell carcinoma, due to induction of genes such as CCND1 and TERT that permit sustained proliferation

[103,104,105]

STAT4

Germline GoF mutation

Autoimmune disorders, due enhanced signaling by IL-12 and other cytokines

[106]

STAT5A

Acquired activating mutation

T cell leukemias, due to increased proliferation and survival

[107]

STAT5B

Germline LoF mutation

Growth hormone insensitivity, immunodeficiency, eczema

[99]

Acquired activating mutation

Multiple T cell leukemias, due to increased proliferation and survival

[102]

STAT5

Hyperactivation due to upstream components

Myeloproliferative neoplasms such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), due to increased proliferation and survival

[108]

Inducible transcriptional repression

STAT1

Loss of expression

Various cancers (melanoma, oesophageal squamous cell carcinoma, lung cancer, breast cancer), due to disruption of tumor suppressor activity of STAT1

[109, 110]

STAT3

Hyperactivation due to upstream components

Chronic lymphocytic leukemia, due to increased repression of TP53 tumor suppressor gene

[72, 111]

STAT5

Loss of STAT5-binding sites

Various B cell malignancies caused by constitutive expression of BCL6A that is normally repressed by STAT5

[112, 113]

Basal transcriptional activation

STAT3

Overexpression due to upstream components

Various cancers due to increased expression of oncogenes such as CCNB1 and E2F11 via excessive uSTAT3

[73]

STAT6

Overexpression due to upstream components

Hepatocellular carcinoma due to increased cyclooxygenase-2 expression via excessive uSTAT6

[114, 115]

Inducible non-nuclear roles

STAT5

Hyperactivation due to upstream components

Interacts with scaffold adaptor to mediate cell survival and metabolism of cancer cells

[76, 116]