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	Vol	Issue	Date	Pages	Journal Short Title
The Journal of biological chemistry	290	48	2015 Nov 27	29022-34	J Biol Chem

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

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
JAK3	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).
JAK3	L857P	missense	gain of function	JAK3 L857P lies within protein kinase domain 2 of the Jak3 protein (UniProt.org). L857P results in cytokine receptor complex-independent activation of Jak3, increased cell proliferation (PMID: 26446793), and cytokine-independent growth in culture (PMID: 35411095).
JAK3	L875H	missense	gain of function	JAK3 L875H lies within protein kinase domain 2 of the Jak3 protein (UniProt.org). L875H results in transforming activity (PMID: 29187379), receptor-independent Jak3 activation (PMID: 26446793), and demonstrates resistance to some JAK inhibitors in culture (PMID: 31976485).	Y
JAK3	P906S	missense	gain of function - predicted	JAK3 P906S lies within protein kinase domain 2 of the Jak3 protein (UniProt.org). P906S results in increased cytokine receptor complex-dependent activation of Jak3 in cell culture (PMID: 26446793), and therefore, is predicted to lead to a gain of Jak3 protein function.
JAK3	T848A	missense	gain of function - predicted	JAK3 T848A lies within protein kinase domain 2 of the Jak3 protein (UniProt.org). T848A results in cytokine receptor complex-dependent activation of Jak3 in cell culture (PMID: 26446793), and therefore, is predicted to lead to a gain of Jak3 protein function.

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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	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 Y100A JAK3 L857P	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 Y100A 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 both JAK3 L857P and Y100A 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 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
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 Y100A 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 both JAK3 L857P and Y100A in culture (PMID: 26446793).	26446793