Impact of FLT3-ITD diversity on response to induction chemotherapy in patients with acute myeloid leukemia

Fischer, Mike; Schnetzke, Ulf; Spies-Weisshart, Bärbel; Walther, Mario; Fleischmann, Maximilian; Hilgendorf, Inken; Hochhaus, Andreas; Scholl, Sebastian

doi:10.3324/haematol.2016.157180

Cited by 21 publications

(20 citation statements)

References 15 publications

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“…FLT3-ITD + AML cell lines were most sensitive to STAT5 inhibition, emphasizing the importance of STAT5 in the maintenance and survival of cells with this particular driver mutation [ 12 ]. Our findings are supported by the analysis of primary AML samples, where AC-4–130 caused a significant decrease in cell viability and inhibition of colony formation.…”

Section: Discussionmentioning

confidence: 99%

“…Activating mutations in the FLT3 receptor TK represent the most frequent mutations in AML, affecting 28% of all patients [ 10 , 11 ]. The most common class of FLT3- mutations are internal tandem duplications (ITDs) [ 12 ]. FLT3-ITD mutations lead to constitutive, ligand-independent activation of the kinase [ 13 ], and persistent activation of downstream signaling pathways involving PI3K-AKT, RAS-MAPK, and STAT5.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacologic inhibition of STAT5 in acute myeloid leukemia

et al. 2018

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The transcription factor STAT5 is an essential downstream mediator of many tyrosine kinases (TKs), particularly in hematopoietic cancers. STAT5 is activated by FLT3-ITD, which is a constitutively active TK driving the pathogenesis of acute myeloid leukemia (AML). Since STAT5 is a critical mediator of diverse malignant properties of AML cells, direct targeting of STAT5 is of significant clinical value. Here, we describe the development and preclinical evaluation of a novel, potent STAT5 SH2 domain inhibitor, AC-4–130, which can efficiently block pathological levels of STAT5 activity in AML. AC-4–130 directly binds to STAT5 and disrupts STAT5 activation, dimerization, nuclear translocation, and STAT5-dependent gene transcription. Notably, AC-4–130 substantially impaired the proliferation and clonogenic growth of human AML cell lines and primary FLT3-ITD+ AML patient cells in vitro and in vivo. Furthermore, AC-4–130 synergistically increased the cytotoxicity of the JAK1/2 inhibitor Ruxolitinib and the p300/pCAF inhibitor Garcinol. Overall, the synergistic effects of AC-4–130 with TK inhibitors (TKIs) as well as emerging treatment strategies provide new therapeutic opportunities for leukemia and potentially other cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmacologic inhibition of STAT5 in acute myeloid leukemia

et al. 2018

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“…Interestingly, the clinical response correlated with the post-treatment FLT3 -ITD MRD levels, evaluated by NGS [ 61 ]. In addition, the identification of the ITD position by NGS approaches might be of prognostic relevance considering the impact of FLT3 -ITD insertion site on therapy resistance and outcome – for conventional chemotherapy as well as for TKI treatment [ 10 , 16 – 21 ]. However, the clinical relevance of ITD position still remains controversial [ 22 , 24 , 25 , 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…[ 13 – 15 ] FLT3 -ITDs are predominately located in exon 14 and 15, affecting the juxtamembrane domain (JM) and tyrosine kinase domain 1 (TKD1) of the FLT3 receptor [ 16 ]. Depending on the FLT3 -ITD insertion site and respective functional domain, differential outcome and response to treatment with conventional chemotherapy as well as TKIs were observed; especially non-JM ITDs displayed a resistance to TKIs [ 10 , 16 – 21 ]. Although always leading to an in-frame transcript, FLT3 -ITDs vary in length (between three to over 400 nucleotides (nt)) and sequence [ 1 , 2 , 4 , 6 , 17 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Clonal heterogeneity of FLT3-ITD detected by high-throughput amplicon sequencing correlates with adverse prognosis in acute myeloid leukemia

et al. 2018

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In acute myeloid leukemia (AML), internal tandem duplications (ITDs) of FLT3 are frequent mutations associated with unfavorable prognosis. At diagnosis, the FLT3-ITD status is routinely assessed by fragment analysis, providing information about the length but not the position and sequence of the ITD. To overcome this limitation, we performed cDNA-based high-throughput amplicon sequencing (HTAS) in 250 FLT3-ITD positive AML patients, treated on German AML Cooperative Group (AMLCG) trials. FLT3-ITD status determined by routine diagnostics was confirmed by HTAS in 242 out of 250 patients (97%). The total number of ITDs detected by HTAS was higher than in routine diagnostics (n = 312 vs. n = 274). In particular, HTAS detected a higher number of ITDs per patient compared to fragment analysis, indicating higher sensitivity for subclonal ITDs. Patients with more than one ITD according to HTAS had a significantly shorter overall and relapse free survival. There was a close correlation between FLT3-ITD mRNA levels in fragment analysis and variant allele frequency in HTAS. However, the abundance of long ITDs (≥75nt) was underestimated by HTAS, as the size of the ITD affected the mappability of the corresponding sequence reads. In summary, this study demonstrates that HTAS is a feasible approach for FLT3-ITD detection in AML patients, delivering length, position, sequence and mutational burden of this alteration in a single assay with high sensitivity. Our findings provide insights into the clonal architecture of FLT3-ITD positive AML and have clinical implications.

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“…1 The mutation of FMS-like receptor tyrosine kinase 3 (FLT3) occurs in about 1/3 of patients with acute myeloid leukemia, and its internal tandem mutation (ITD) often leads to rapid disease progression and poor prognosis. 2,3 To improve the prognosis of FLT3-ITD+patients, many FLT3 inhibitors have been published, but these drugs have limited efficacy. The recurrence rate of patients treated with single drug is close to 100%.…”

Section: Introductionmentioning

confidence: 99%

<p>Long Noncoding RNA SOCS2-AS Promotes Leukemogenesis in FLT3-ITD+ Acute Myeloid Leukemia Through miRNA-221</p>

Zhang¹,

Huo²

2020

OTT

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Background: LncRNAs play an important role in tumorigenesis and development in tumors, but the function of lncRNA SOCS2-AS in acute myeloid leukemia (AML) is unknown. Materials and Methods: In the present study, we used RT-PCR to detect the expression of SOCS2-AS in FLT3-ITD+, FLT3-ITD-AML patients and different AML cell lines. The colony formation and CCK-8 assay were performed to analyze the proliferation ability, and the flow cytometry was performed to analyze the capacity of apoptosis in Molm-13 and MV4-11 cells. The Western blot was applied to detect the expression of STAT5 and p-STAT5. The RNA pulldown and luciferase activity were used to investigate the interaction between SOCS2-AS and miR-221. Results: The results indicate that SOCS2-AS shows overexpression in FLT3-ITD+ AML patients compared to FLT3-ITD-AML patients. Si-SOCS2-AS can inhibit the proliferation, boost the apoptosis and induce the cycle arrest in Molm-13 cells, and SOCS2-AS overexpression promotes proliferation and colony formation in MV4-11 cells. The miR-221 shows overexpression in FLT3-ITD+ AML patients compared to FLT3-ITD-AML patients. And the expression level of miR-221 and SOCS2-AS shows negative correlation in FLT3-ITD+ AML patients. Functionally, SOCS2-AS could be interacted with miR-221 in AML cells. After SOCS2-AS knockdown, the phosphorylation level of STAT5 was significantly decreased. Moreover, miR-221 inhibitor can rescue the viability in cells after si-SOCS2-AS transfection. And it is stated that SOCS2-AS regulates the STAT5 signal transduction pathway with sponging miR-221. Conclusion: In conclusion, this study confirms the molecular mechanism of SOCS2-AS in AML by targeting the miR-221/STAT5 signaling pathway. This indicates SOCS2-AS may serve as a potential therapeutic target for the treatment of AML.

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Impact of FLT3-ITD diversity on response to induction chemotherapy in patients with acute myeloid leukemia

Cited by 21 publications

References 15 publications

Pharmacologic inhibition of STAT5 in acute myeloid leukemia

Pharmacologic inhibition of STAT5 in acute myeloid leukemia

Clonal heterogeneity of FLT3-ITD detected by high-throughput amplicon sequencing correlates with adverse prognosis in acute myeloid leukemia

<p>Long Noncoding RNA SOCS2-AS Promotes Leukemogenesis in FLT3-ITD+ Acute Myeloid Leukemia Through miRNA-221</p>

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