Reference Detail

Ref Type Journal Article
PMID (26446793)
Authors Losdyck E, Hornakova T, Springuel L, Degryse S, Gielen O, Cools J, Constantinescu SN, Flex E, Tartaglia M, Renauld JC, Knoops L
Title Distinct Acute Lymphoblastic Leukemia (ALL)-associated Janus Kinase 3 (JAK3) Mutants Exhibit Different Cytokine-Receptor Requirements and JAK Inhibitor Specificities.
Journal The Journal of biological chemistry
Vol 290
Issue 48
Date 2015 Nov 27
URL
Abstract Text JAK1 and JAK3 are recurrently mutated in acute lymphoblastic leukemia. These tyrosine kinases associate with heterodimeric cytokine receptors such as IL-7 receptor or IL-9 receptor, in which JAK1 is appended to the specific chain, and JAK3 is appended to the common gamma chain. Here, we studied the role of these receptor complexes in mediating the oncogenic activity of JAK3 mutants. Although JAK3(V674A) and the majority of other JAK3 mutants needed to bind to a functional cytokine receptor complex to constitutively activate STAT5, JAK3(L857P) was unexpectedly found to not depend on such receptor complexes for its activity, which was induced without receptor or JAK1 co-expression. Introducing a mutation in the FERM domain that abolished JAK-receptor interaction did not affect JAK3(L857P) activity, whereas it inhibited the other receptor-dependent mutants. The same cytokine receptor independence as for JAK3(L857P) was observed for homologous Leu(857) mutations of JAK1 and JAK2 and for JAK3(L875H). This different cytokine receptor requirement correlated with different functional properties in vivo and with distinct sensitivity to JAK inhibitors. Transduction of murine hematopoietic cells with JAK3(V674A) led homogenously to lymphoblastic leukemias in BALB/c mice. In contrast, transduction with JAK3(L857P) induced various types of lymphoid and myeloid leukemias. Moreover, ruxolitinib, which preferentially blocks JAK1 and JAK2, abolished the proliferation of cells transformed by the receptor-dependent JAK3(V674A), yet proved much less potent on cells expressing JAK3(L857P). These particular cells were, in contrast, more sensitive to JAK3-specific inhibitors. Altogether, our results showed that different JAK3 mutations induce constitutive activation through distinct mechanisms, pointing to specific therapeutic perspectives.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
E958K missense gain of function JAK3 E958K lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). E958K confers a gain of function to the Jak3 protein, as demonstrated by increased cytokine receptor complex-dependent activation of Jak3 in cell culture (PMID: 26446793), activation of Stat5, and is transforming in cell culture (PMID: 26206799).
L857H missense gain of function - predicted JAK3 L857H lies within the protein kinase domain 2 of the Jak3 proteim (UniProt.org). L857H is predicted to confer a gain of function to the Jak3 protein, as demonstrated by cytokine receptor complex-independent activation of Jak3 in cell culture (PMID: 26446793).
L857P missense gain of function JAK3 L857P lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). L857P results in cytokine receptor complex-independent activation of Jak3 and increased cell proliferation in culture (PMID: 26446793).
P906S missense gain of function - predicted JAK3 P906S lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). P906Sis predicted to confer a gain of fucntion to the Jak3 protein, as demonstrated by increased cytokine receptor complex-dependent activation of Jak3 in cell culture (PMID: 26446793).
T848A missense gain of function - predicted JAK3 T848A lies within the protein kinase domain 2 of the Jak3 protein (UniProt.org). T848A is predicted to confer a gain of function to the Jak3 protein, as demonstrated by increased cytokine receptor complex-dependent activation of Jak3 in cell culture (PMID: 26446793).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK3 L857P Advanced Solid Tumor sensitive NIBR3049 Preclinical - Cell culture Actionable In a preclinical study, NIBR3049 inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing JAK3 L857P in culture (PMID: 26446793). 26446793
JAK3 V674A Advanced Solid Tumor decreased response NIBR3049 Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing JAK3 V674A demonstrated reduced sensitivity to NIBR3049 in culture (PMID: 26446793). 26446793
JAK3 L857P JAK3 Y100A Advanced Solid Tumor decreased response Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing both JAK3 L857P and JAK3 Y100A demonstrated reduced sensitivity to Jakafi (ruxolitinib) in culture (PMID: 26446793). 26446793
JAK3 V674A Advanced Solid Tumor sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing JAK3 V674A in culture (PMID: 26446793). 26446793
JAK3 L857P Advanced Solid Tumor decreased response Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells over expressing JAK3 L857P demonstrated reduced sensitivity to Jakafi (ruxolitinib) in culture (PMID: 26446793). 26446793
JAK3 L857P JAK3 Y100A Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib) inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing both JAK3 L857P and Y100A in culture (PMID: 26446793). 26446793
JAK3 L857P Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib) inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing JAK3 L857P in culture (PMID: 26446793). 26446793
JAK3 L857P JAK3 Y100A Advanced Solid Tumor sensitive NIBR3049 Preclinical - Cell culture Actionable In a preclinical study, NIBR3049 inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing both JAK3 L857P and Y100A in culture (PMID: 26446793). 26446793
JAK3 V674A Advanced Solid Tumor sensitive Tofacitinib Preclinical - Cell culture Actionable In a preclinical study, Xeljanz (tofacitinib) inhibited Jak3-Stat signaling and cell proliferation in transformed cells over expressing JAK3 V674A in culture (PMID: 26446793). 26446793