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Ref Type | Journal Article | ||||||||||||
PMID | (33149267) | ||||||||||||
Authors | Rummelt C, Gorantla SP, Meggendorfer M, Charlet A, Endres C, Döhner K, Heidel FH, Fischer T, Haferlach T, Duyster J, von Bubnoff N | ||||||||||||
Title | Activating JAK-mutations confer resistance to FLT3 kinase inhibitors in FLT3-ITD positive AML in vitro and in vivo. | ||||||||||||
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Abstract Text | An important limitation of FLT3 tyrosine kinase inhibitors (TKIs) in FLT3-ITD positive AML is the development of resistance. To better understand resistance to FLT3 inhibition, we examined FLT3-ITD positive cell lines which had acquired resistance to midostaurin or sorafenib. In 6 out of 23 TKI resistant cell lines we were able to detect a JAK1 V658F mutation, a mutation that led to reactivation of the CSF2RB-STAT5 pathway. Knockdown of JAK1, or treatment with a JAK inhibitor, resensitized cells to FLT3 inhibition. Out of 136 patients with FLT3-ITD mutated AML and exposed to FLT3 inhibitor, we found seven different JAK family mutations in six of the cases (4.4%), including five bona fide, activating mutations. Except for one patient, the JAK mutations occurred de novo (n = 4) or displayed increasing variant allele frequency after exposure to FLT3 TKI (n = 1). In vitro each of the five activating variants were found to induce resistance to FLT3-ITD inhibition, which was then overcome by dual FLT3/JAK inhibition. In conclusion, our data characterize a novel mechanism of resistance to FLT3-ITD inhibition and may offer a potential therapy, using dual JAK and FLT3 inhibition. |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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FLT3 | R834_D835del | deletion | unknown | FLT3 R834_D835del results in the deletion of two amino acids in the protein kinase domain of the Flt3 protein from amino acids 834 to 835 (UniProt.org). R834_D835del has been identified in sequencing studies (PMID: 31471587, PMID: 33149267), but has not been biochemically characterized and therefore, its effect on Flt3 protein function is unknown (PubMed, May 2025). |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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FLT3 exon 14 ins JAK1 R724H JAK3 A573V | acute myeloid leukemia | resistant | Midostaurin | Case Reports/Case Series | Actionable | In a clinical case study, a patient with acute myeloid leukemia harboring a FLT3-ITD mutation, JAK1 R724H, and JAK3 A573V demonstrated increased allele frequencies for JAK1 R724H (13.5% vs 22%) and JAK3 A573V (13.1% vs 23.1%) after not responding to treatment with Rydapt (midostaurin) and chemotherapy, and in a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation, JAK1 R724H, and JAK3 A573V were resistant to treatment with Rydapt (midostaurin) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 R953* | acute myeloid leukemia | predicted - resistant | Quizartinib | Case Reports/Case Series | Actionable | In a clinical case study, a patient with acute myeloid leukemia harboring a FLT3-ITD mutation treated with Vanflyta (quizartinib) was found to have acquired a JAK3 R953* mutation upon relapse (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 V722I | acute myeloid leukemia | predicted - resistant | Sorafenib | Case Reports/Case Series | Actionable | In a clinical case study, a patient with acute myeloid leukemia harboring a FLT3-ITD mutation treated with Nexavar (sorafenib) was found to have acquired a JAK3 V722I mutation with a variant allele frequency of 49% upon relapse (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 R724H JAK3 A573V | hematologic cancer | resistant | Tofacitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation, JAK1 R724H, and JAK3 A573V were resistant to treatment with Xeljanz (tofacitinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 R724H JAK3 A573V | hematologic cancer | resistant | Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation, JAK1 R724H, and JAK3 A573V were resistant to treatment with Jakafi (ruxolitinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 R724H JAK3 A573V | hematologic cancer | sensitive | Midostaurin + Tofacitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Rydapt (midostaurin) and Xeljanz (tofacitinib) inhibited growth of transformed hematologic cells expressing a FLT3-ITD mutation, JAK1 R724H, and JAK3 A573V in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 R724H JAK3 A573V | hematologic cancer | sensitive | Midostaurin + Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Rydapt (midostaurin) and Jakafi (ruxolitinib) inhibited downstream signaling and cell growth in transformed hematologic cells expressing a FLT3-ITD mutation, JAK1 R724H, and JAK3 A573V in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 S703I | hematologic cancer | resistant | Tofacitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 S703I were resistant to treatment with Xeljanz (tofacitinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 S703I | hematologic cancer | sensitive | Gilteritinib + Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Xospata (gilteritinib) and Jakafi (ruxolitinib) inhibited growth of transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 S703I in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 S703I | hematologic cancer | resistant | Gilteritinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 S703I were resistant to treatment with Xospata (gilteritinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 S703I | hematologic cancer | resistant | Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 S703I were resistant to treatment with Jakafi (ruxolitinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 S703I | hematologic cancer | sensitive | Midostaurin + Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Rydapt (midostaurin) and Jakafi (ruxolitinib) inhibited downstream signaling and cell growth in transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 S703I in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 S703I | hematologic cancer | decreased response | Pacritinib | Preclinical - Cell culture | Actionable | In a preclinical study, Vonjo (pacritinib) treatment decreased cell proliferation and Akt and Erk phosphorylation, but did not fully inhibit Stat5 phosphorylation in transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 S703I and was less effective compared to treatment with the combination of a FLT3 inhibitor and a JAK inhibitor in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 S703I | acute myeloid leukemia | resistant | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 S703I were resistant to treatment with Rydapt (midostaurin) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 S703I | hematologic cancer | sensitive | Midostaurin + Tofacitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Rydapt (midostaurin) and Xeljanz (tofacitinib) inhibited growth of transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 S703I in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 V658F | hematologic cancer | sensitive | Midostaurin + Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Rydapt (midostaurin) and Jakafi (ruxolitinib) inhibited Flt3 and Stat5 phosphorylation and growth of transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 V658F in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 V658F | hematologic cancer | resistant | Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 V658F were resistant to treatment with Nexavar (sorafenib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 V658F | hematologic cancer | resistant | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 V658F were resistant to treatment with Rydapt (midostaurin) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 V658F | hematologic cancer | resistant | Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 V658F were resistant to treatment with Jakafi (ruxolitinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK1 V658F | hematologic cancer | sensitive | Ruxolitinib + Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Nexavar (sorafenib) and Jakafi (ruxolitinib) inhibited growth of transformed hematologic cells expressing a FLT3-ITD mutation and JAK1 V658F in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK2 V617F | hematologic cancer | sensitive | Midostaurin + Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Rydapt (midostaurin) and Jakafi (ruxolitinib) inhibited downstream signaling and cell growth in transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK2 V617F | hematologic cancer | sensitive | Gilteritinib + Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Xospata (gilteritinib) and Jakafi (ruxolitinib) inhibited growth of transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK2 V617F | hematologic cancer | resistant | Tofacitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F were resistant to treatment with Xeljanz (tofacitinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK2 V617F | hematologic cancer | resistant | Gilteritinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F were resistant to treatment with Xospata (gilteritinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK2 V617F | hematologic cancer | resistant | Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F were resistant to treatment with Jakafi (ruxolitinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK2 V617F | hematologic cancer | resistant | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F were resistant to treatment with Rydapt (midostaurin) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK2 V617F | hematologic cancer | decreased response | Midostaurin + Tofacitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F demonstrated a decreased response to treatment with the combination of Rydapt (midostaurin) and Xeljanz (tofacitinib) compared to cells expressing a FLT3-ITD mutation and activating mutations of JAK1 or JAK3 in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK2 V617F | hematologic cancer | predicted - sensitive | Pacritinib | Preclinical - Cell culture | Actionable | In a preclinical study, Vonjo (pacritinib) treatment decreased cell proliferation and downstream signaling in transformed hematologic cells expressing a FLT3-ITD mutation and JAK2 V617F in culture but may not be capable of fully inhibiting Flt3 and Jak signaling at clinically achievable concentrations (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 R953* | hematologic cancer | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited growth of transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 R953* in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 V722I | hematologic cancer | resistant | Gilteritinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I were resistant to treatment with Xospata (gilteritinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 V722I | hematologic cancer | sensitive | Midostaurin + Tofacitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Rydapt (midostaurin) and Xeljanz (tofacitinib) inhibited cell growth and downstream signaling of transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 V722I | hematologic cancer | decreased response | Pacritinib | Preclinical - Cell culture | Actionable | In a preclinical study, Vonjo (pacritinib) treatment decreased cell proliferation and Akt and Erk phosphorylation, but did not fully inhibit Stat5 phosphorylation in transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I and was less effective compared to treatment with the combination of a FLT3 inhibitor and a JAK inhibitor in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 V722I | hematologic cancer | sensitive | Gilteritinib + Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Xospata (gilteritinib) and Jakafi (ruxolitinib) inhibited growth of transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 V722I | hematologic cancer | resistant | Tofacitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I were resistant to treatment with Xeljanz (tofacitinib) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 V722I | hematologic cancer | sensitive | Midostaurin + Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Rydapt (midostaurin) and Jakafi (ruxolitinib) inhibited downstream signaling and cell growth in transformed hematologic cells expressing aa FLT3-ITD mutation and JAK3 V722I in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 V722I | hematologic cancer | resistant | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I were resistant to treatment with Rydapt (midostaurin) in culture (PMID: 33149267). | 33149267 |
FLT3 exon 14 ins JAK3 V722I | hematologic cancer | resistant | Ruxolitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed hematologic cells expressing a FLT3-ITD mutation and JAK3 V722I were resistant to treatment with Jakafi (ruxolitinib) in culture (PMID: 33149267). | 33149267 |
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