Targeting AML-associated FLT3 mutations with a type I kinase inhibitor

Jones, LaQuita M; Melgar, Katelyn; Bolanos, Lyndsey; Hueneman, Kathleen; Walker, Morgan M.; Jiang, Jian‐kang; Wilson, Kelli; Zhang, Xiaohu; Shen, Jian; Jiang, Fan; Sutter, Patrick; Wang, Amy; Xu, Xin; Tawa, Gregory J.; Hoyt, Scott B.; Wunderlich, Mark; O’Brien, Eric; Perentesis, John P.; Starczynowski, Daniel T.; Thomas, Craig J.

doi:10.1172/jci127907

Cited by 25 publications

(26 citation statements)

References 21 publications

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“…AML is a malignant haematological disorder, with a rise in prevalence with age, and 70% of patients also die from the disease diagnosed [26]. Immune therapy advances have been met with many challenges for children and adults with AML, including lack of identified tumor-specific antiquities, interand intrapatient disease heterogeneity [27], as well as greater Journal of Oncology understanding of microenvironmental factors impeding the therapeutic effectiveness of immunosuppressive bone marrows [28]. Until now, checkpoint inhibitors in the pediatric leukemia community have been minimally examined.…”

Section: Discussionmentioning

confidence: 99%

An Immune Checkpoint-Related Gene Signature for Predicting Survival of Pediatric Acute Myeloid Leukemia

Jiang

Wang

et al. 2021

Journal of Oncology

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Objective. The aim of this research was to create a new genetic signature of immune checkpoint-associated genes as a prognostic method for pediatric acute myeloid leukemia (AML). Methods. Transcriptome profiles and clinical follow-up details were obtained in Therapeutically Applicable Research to Generate Effective Treatments (TARGET), a database of pediatric tumors. Secondary data was collected from the Gene Expression Omnibus (GEO) to test the observations. In univariate Cox regression and multivariate Cox regression studies, the expression of immune checkpoint-related genes was studied. A three-mRNA signature was developed for predicting pediatric AML patient survival. Furthermore, the GEO cohort was used to confirm the reliability. A bioinformatics method was utilized to identify the diagnostic and prognostic value. Results. A three-gene (STAT1, BATF, EML4) signature was developed to identify patients into two danger categories depending on their OS. A multivariate regression study showed that the immune checkpoint-related signature (STAT1, BATF, EML4) was an independent indicator of pediatric AML. By immune cell subtypes analyses, the signature was correlated with multiple subtypes of immune cells. Conclusion. In summary, our three-gene signature can be a useful tool to predict the OS in AML patients.

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Section: Discussionmentioning

confidence: 99%

An Immune Checkpoint-Related Gene Signature for Predicting Survival of Pediatric Acute Myeloid Leukemia

Jiang

Wang

et al. 2021

Journal of Oncology

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“…NIH does not prescribe a specific number of publications as a benchmark, instead focusing on publication quality, rigor, innovativeness, and impact. A few recent examples illustrate these features in DPI's publications: a serosurvey of COVID-19 [25]; molecular targets and pathways for organ level toxicity [26]; computational methods in metabolomics [27]; targeting cancer mutations with kinase inhibitors [28]; and therapeutic candidates for the Zika virus [29]. These publications [25][26][27][28][29] demonstrate the quality and public health impact of the research.…”

Section: Discussionmentioning

confidence: 97%

“…A few recent examples illustrate these features in DPI's publications: a serosurvey of COVID-19; 25 molecular targets and pathways for organ level toxicity; 26 computational methods in metabolomics; 27 targeting cancer mutations with kinase inhibitors; 28 and therapeutic candidates for the Zika virus. 29 These publications [25][26][27][28][29] demonstrate the quality and public health impact of the research. Table 2 links the major findings of these studies to the performance metrics in Figure 2, providing a deeper analysis of the scientific contributions of the studies represented in this sample of DPI manuscripts.…”

Section: Discussionmentioning

confidence: 99%

A systems approach to enable effective team science from the internal research program of the National Center for Advancing Translational Sciences

Vogel

Knebel

Faupel-Badger

et al. 2021

J. Clin. Trans. Sci.

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“…However, it is not clear how activation of FLT3-WT confers resistance. Nonetheless, an altered signaling network engaged by FLT3-WT supporting survival during TKI therapy is postulated possibly exploiting the cell-intrinsic inflammatory-related pathways for survival 45,46 . Likewise, cytokine-induced activation of Jak2 signaling confers resistance 22 .…”

Section: Discussionmentioning

confidence: 99%

Momelotinib is a highly potent inhibitor of FLT3-mutant AML

Azhar

Kincaid

Kesarwani

et al. 2021

Preprint

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Kinase activating mutation in FLT3 is the most frequent genetic lesion associated with poor prognosis in acute myeloid leukemia (AML). Therapeutic response to FLT3 tyrosine kinase inhibitor (TKI) therapy is dismal, and many patients relapse even after allogenic stem cell transplantation. Despite the introduction of more selective FLT3 inhibitors, remissions are short-lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic mutations and growth factor signaling are two principal mechanisms that drive relapse. FLT3 inhibitors targeting both escape mechanisms could lead to a more profound and lasting clinical responses. Here we show that the JAK2 inhibitor, momelotinib, is an equipotent type-1 FLT3 inhibitor. Momelotinib showed potent inhibitory activity on both mouse and human cells expressing FLT3-ITD, including clinically relevant resistant mutations within the activation loop at residues, D835, D839, and Y842. Additionally, momelotinib efficiently suppressed the resistance mediated by FLT3 ligand (FL) and hematopoietic cytokine activated JAK2 signaling. Interestingly, unlike gilteritinib, momelotinib inhibits the expression of MYC in leukemic cells. Consequently, concomitant inhibition of FLT3 and downregulation of MYC by momelotinib treatment showed better efficacy in suppressing the leukemia in a preclinical murine model of AML. Altogether, these data provide evidence that momelotinib is an effective type-1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response; thus, warrants its clinical evaluation.Key pointsMomelotinib shows high efficacy against FLT3 mutated AML cells including quizartinib-resistant activation loop variants.Momelotinib effectively suppresses intrinsic resistance conferred by FLT3 ligand and hematopoietic cytokines (GM-CSF and IL3).

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Targeting AML-associated FLT3 mutations with a type I kinase inhibitor

Cited by 25 publications

References 21 publications

An Immune Checkpoint-Related Gene Signature for Predicting Survival of Pediatric Acute Myeloid Leukemia

An Immune Checkpoint-Related Gene Signature for Predicting Survival of Pediatric Acute Myeloid Leukemia

A systems approach to enable effective team science from the internal research program of the National Center for Advancing Translational Sciences

Momelotinib is a highly potent inhibitor of FLT3-mutant AML

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