Monocytic Maturation Induced by FLT3 Inhibitor Therapy of Acute Myeloid Leukemia: Morphologic and Immunophenotypic Characteristics

2019 ◽  
Vol 51 (5) ◽  
pp. 478-483
Author(s):  
Cade D Arries ◽  
Sophia L Yohe
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Cell Population ◽  
Myeloid Leukemia ◽  
Inhibitor Therapy ◽  
Molecular Abnormalities ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Abstract Background FMS-like tyrosine kinase-3 (FLT3-ITD) mutations are some of the most common mutations in acute myeloid leukemia (AML), and patient outcomes have improved since the advent of tyrosine kinase inhibitors. First, granulocytic differentiation was described in FLT3-positive AML treated with FLT3 inhibitors, and more recently, monocytic differentiation was reported. Methods Two patients with myelomonocytic cells in their bone marrow were identified during routine follow-up after AML treatment that included FLT3 inhibitors. The bone marrow study was done as standard of care. Results Both patients had FLT3-ITD+ AML and showed an atypical maturing monocytic cell population and a decrease in the leukemic blast cell population after FLT3 inhibitor therapy. Concurrent genetic testing revealed persistent genetic abnormalities. Conclusions These cases illustrate monocytic maturation in FLT3+ AML after FLT3 inhibitor treatment. It is critical for pathologists and clinicians to be aware of the differentiation phenomenon, as these patients have persistent molecular abnormalities despite response to treatment and normalization of blast counts.

scholarly journals ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

2016 ◽  
Vol 113 (43) ◽  
pp. E6669-E6678 ◽  
Author(s):  
Mark A. Gregory ◽  
Angelo D’Alessandro ◽  
Francesca Alvarez-Calderon ◽  
Jihye Kim ◽  
Travis Nemkov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mitochondrial Oxidative Stress ◽  
Flt3 Inhibitor ◽  
A Genome ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

scholarly journals Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2493
Author(s):  
Sebastian Scholl ◽  
Maximilian Fleischmann ◽  
Ulf Schnetzke ◽  
Florian H. Heidel
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Continuous Treatment ◽  
Next Generation ◽  
Secondary Resistance ◽  
Development Of Resistance ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Treatment of FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD)-positive acute myeloid leukemia (AML) remains a challenge despite the development of novel FLT3-directed tyrosine kinase inhibitors (TKI); the relapse rate is still high even after allogeneic stem cell transplantation. In the era of next-generation FLT3-inhibitors, such as midostaurin and gilteritinib, we still observe primary and secondary resistance to TKI both in monotherapy and in combination with chemotherapy. Moreover, remissions are frequently short-lived even in the presence of continuous treatment with next-generation FLT3 inhibitors. In this comprehensive review, we focus on molecular mechanisms underlying the development of resistance to relevant FLT3 inhibitors and elucidate how this knowledge might help to develop new concepts for improving the response to FLT3-inhibitors and reducing the development of resistance in AML. Tailored treatment approaches that address additional molecular targets beyond FLT3 could overcome resistance and facilitate molecular responses in AML.

Recent advances in FLT3 inhibitors for acute myeloid leukemia

2020 ◽  
Vol 12 (10) ◽  
pp. 961-981 ◽  
Author(s):  
Lexian Tong ◽  
Xuemei Li ◽  
Yongzhou Hu ◽  
Tao Liu
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Clinical Stage ◽  
Wild Type ◽  
New Techniques ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Target Activity ◽  
Acute Myeloid

Fms-like tyrosine kinase-3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) cases, suggesting FLT3 as an attractive target for AML treatment. Early FLT3 inhibitors enhance antileukemia efficacy by inhibiting multiple targets, and thus had stronger off-target activity, increasing their toxicity. Recently, a number of potent and selective FLT3 inhibitors have been developed, many of which are effective against multiple mutations. This review outlines the evolution of AML-targeting FLT3 inhibitors by focusing on their chemotypes, selectivity and activity over FLT3 wild-type and FLT3 mutations as well as new techniques related to FLT3. Compounds that currently enter the late clinical stage or have entered the market are also briefly reported.

scholarly journals Treatment with FLT3 inhibitor in patients withFLT3-mutated acute myeloid leukemia is associated with development of secondaryFLT3-tyrosine kinase domain mutations

Cancer ◽  
2014 ◽  
Vol 120 (14) ◽  
pp. 2142-2149 ◽  
Author(s):  
Yesid Alvarado ◽  
Hagop M. Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Flt3 Inhibitor ◽  
Kinase Domain Mutations ◽  
Acute Myeloid

Activating Mutations of the FMS-Like Tyrosine Kinase-3 (FLT3) At Complete Response and Relapse in Patients with Acute Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3557-3557
Author(s):  
Aziz Nazha ◽  
Jorge E. Cortes ◽  
Stefan Faderl ◽  
Sherry Pierce ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Complete Response ◽  
Entire Group ◽  
Trisomy 8 ◽  
Activating Mutations ◽  
Acute Myeloid

Abstract Abstract 3557 Background – Activating mutations of the transmembrane receptor tyrosine kinase, FLT3, occur in approximately 30% of patient with acute myeloid leukemia (AML) and predict for a shorter relapse-free and overall survival. There is limited data on loss or persistence of the mutated clones at the time of complete response (CR) and their recurrence at the time of relapse. Objectives and Methods – To evaluate patterns of loss and recurrence of FLT3 mutated clones in relation to response and relapse in patients with FLT3 mutated AML treated with idarubicin and cytarabine (IA) with or without sorafenib (S), vorinostat (V), or tipifarnib (T). Bone marrow samples at diagnosis, CR and relapse were examined for the presence of FLT3 mutated clones using reverse transcription polymerase chain reaction. Results – Among 361 patients with AML treated from October 2004 to March 2010 on one of the 4 induction regimens of IA, IAS, IAV, and IAT, 321 had presentation bone marrow samples tested and 72 had FLT3 mutations (including 50 with ITD and 16 D835 with 6 having both). The median age for the entire group was 53 years (range, 17–73) and for the FLT3 mutated patients 52 years (range, 17 to 73). Cytogenetics at diagnosis in FLT3 mutated patients included normal karyotype in 48 (67%) patients, chromosome 5 and 7 abnormalities in 4(6%), trisomy 8 in 4(6%), 11q abnormalities in 2 (3%), insufficient metaphases in 3(4%), and miscellaneous in 11(16%). 271 (75%) patients overall, and 64 (89%) patients with mutated FLT3 achieved CR. Among the 56 patients with presentation FLT3-ITD, 51 achieved CR. Among 13 patients with available samples at CR, none had FLT3-ITD; 8 of these patients relapsed and 5 had FLT3-ITD positive clones at relapse (2 negative and 1 not done); Among the 38 patients with no samples at CR, 17 relapsed, 8 with a FLT3-ITD clone (1 negative and 8 not done). Among the 201 patients without FLT3-ITD at diagnosis, who achieved CR, 8 patients acquired a clone with FLT3-ITD at relapse. Conclusions – FLT3-ITD mutant clones are unstable at follow-up. Relapse may occur in their absence and they may occur for the first time at relapse. Therefore, FLT3-ITD cannot be used reliably for minimal residual leukemia monitoring. Disclosures: Ravandi: Bayer Onyx: Honoraria, Research Funding.

Go6976, a Potent FLT3 Kinase Inhibitor, Exerts Antiproliferative Activity Against Acute Myeloid Leukemia Via Inhibition Of Survivin and Mcl-1 In The Presence Of Human Serum

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3839-3839
Author(s):  
Akira Yoshida ◽  
Kouichi Zokumasu ◽  
Takanori Ueda
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Human Serum ◽  
Inhibitory Activity ◽  
Myeloid Leukemia ◽  
Human Leukemia ◽  
Acid Glycoprotein ◽  
Flt3 Inhibitors ◽  
Ic50 Values ◽  
Acute Myeloid

Abstract The FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in hematopoietic progenitor cell development. Mutations of FLT3 have been reported in about a third of patients with acute myeloid leukemia (AML). The presence of FLT3 mutations confers a poor prognosis, and thus recent studies are directed at developing and testing novel FLT3 inhibitors for the treatment of AML. Go6976 is an indolocarbazole with a simillar structural backbone to staurosporine. In the present study, we demonstrated that Go6976 displays a potent inhibitory activity against recombinant FLT3 using in vitro kinase assay. Its IC50 value is 0.7nM. We also tested the effect of Go6976 on several kinds of other kinases. Go6976 inhibited the kinase activity of Aurora-A, Aurora-B and JAK2 with IC50 values of 118.2 nM, 77.7 nM and 92.7 nM, respectively. Go6976 did not show the inhibitory activity against the FGFR3 even at 1 microM. These data indicated Go6976 preferentially and potently inhibit the FLT3. Go6976 significantly inhibited the proliferation of human leukemia cells having FLT3-ITD. The IC50 values of Go6976 against MV4-11 and MOLM-13 were 0.044 and 0.008 microM, respectively. In contrast, human leukemia HL-60 and U937 cells which lack FLT3-ITD showed strong resistance to Go6976 treatment. Furthermore, we observed that Go6976 shows minimal toxicity for purified human normal CD34(+) cells. Go6976 suppressed the phosphorylation of FLT3 in MV4-11 and MOLM13 cells. Consistent with FLT3 inhibition, Go6976 potently inhibited phosphorylation of constitutively activated STAT3/5, Erk1/2, and Akt. Western blotting analysis revealed that MV4-11 and MOLM13 cells possess abundant survivin and Mcl-1 protein. We hypothesized that the expression of survivin and Mcl-1 may be regulated by constitutive activation of FLT3. In order to test this hypothesis, the effect of siRNA for FLT3-ITD was examined. Indeed, we observed that siRNA-induced down-regulation of FLT3 decreased survivin and Mcl-1 expression in MOLM13 cells, suggesting that up-regulated survivin and Mcl-1 may be closely associated with FLT3 signaling. Interestingly, we found that both survivin mRNA and protein were rapidly downregulated by Go6976 treatment in MOLM13 and MV4-11 cells. It was also observed that Go6976 significantly suppressed Mcl-1 mRNA and protein. It has been reported that STAT-3 and STAT-5 signaling play a pivotal role in the regulation of survivin and Mcl-1, respectively. Thus, inhibitory effects of Go6976 on the expression Survivin and Mcl-1 may be a consequence of the suppression of phosphorylation of STAT-3 and STAT-5 by Go6976 in FLT3-ITD cells. This inhibition of anti-apoptotic proteins by Go6976 may be critical for its antiproliferative effect in FLT3-ITD cells. It has been known that previous FLT3 inhibitors such as PKC412 and CEP-701 bind to the human plasma protein, alpha1-acid glycoprotein, resulting in significantly diminished inhibitory activity against FLT3. Indeed, inhibitory effect of PKC412 on FLT3 was significantly decreased, when MOLM13 cells were treated with PKC412 in the presence of human serum. In contrast, we found that Go6976 potently inhibits phosphorylation of FLT3 and exerts cytotoxicity even in the presence of human serum or human alpha1-acid glycoprotein. In conclusion, our data indicate that Go6976 may have a unique therapeutic potential for FLT3-driven acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo

Blood ◽  
2011 ◽  
Vol 117 (12) ◽  
pp. 3286-3293 ◽  
Author(s):  
Takashi Sato ◽  
Xiaochuan Yang ◽  
Steven Knapper ◽  
Paul White ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Therapeutic Strategy ◽  
Newly Diagnosed ◽  
Flt3 Ligand ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

AbstractWe examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated FLT3 inhibition and cytotoxicity for each of 5 different FLT3 inhibitors (lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220). The dramatic increase in FL level after chemotherapy represents a possible obstacle to inhibiting FLT3 in this clinical setting. These findings could have important implications regarding the design and outcome of trials of FLT3 inhibitors and furthermore suggest a rationale for targeting FL as a therapeutic strategy.

scholarly journals Autophagy Activation Induces Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia with FLT3-ITD Mutation

2021 ◽  
Author(s):  
Dan Xu ◽  
Zhao Yin ◽  
Ying Yang ◽  
Yishan Chen ◽  
Changfen Huang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Critical Role ◽  
Leukemic Cells ◽  
Sorafenib Treatment ◽  
Downstream Signaling ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Inhibitor Resistance ◽  
Acute Myeloid

Abstract Background: Autophagy plays a critical role in drug resistance in acute myeloid leukemia (AML), including the subtype with FLT3-ITD mutation. Yet how autophagy is activated and mediates resistance to FLT3 inhibitors in FLT3-ITD-positive AML remains unsure. Methods: We detected the alteration of autophagy in FLT3-ITD-positive leukemic cells after versus before acquired resistance to FLT3 inhibitors; tested the stimulative effect of acquired D835Y mutation and bone marrow micro-environment (BME) on autophagy; explored the mechanism of autophagy mediating FLT3 inhibitor resistance. Results: Sorafenib-resistant cells markedly overexpressed autophagy in comparison with sorafenib-sensitive cells or the cells before sorafenib treatment. Both acquired D835Y mutation and BME activated cytoprotective autophagy to induce FLT3 inhibitor resistance. Autophagy activation decreased the suppression efficacy of FLT3 inhibitors on FLT3 downstream signaling and then weakened their anti-leukemia effect. Inhibition of autophagy with CQ significantly enhanced the suppressive effect of FLT3 inhibitor on FLT3 downstream signaling, in the end overcame FLT3 inhibitor resistance. Conclusions: Autophagy might be stimulated by acquired mutation or BME, and bypass activate FLT3 downstream signaling to mediate FLT3 inhibitor resistance in FLT3-ITD-positive AML. Targeting autophagy could be a promising strategy to overcome resistance.

CLI24-001: First-in-human study of SEL24/MEN1703, an oral dual PIM/FLT3 kinase inhibitor, in patients with acute myeloid leukemia.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7062-TPS7062
Author(s):  
Farhad Ravandi ◽  
Stephen Anthony Strickland ◽  
Scott R. Solomon ◽  
Aziz Nazha ◽  
Roland B. Walter ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
White Blood Count ◽  
Phase 2 ◽  
Dual Inhibitor ◽  
Pim Kinases ◽  
Flt3 Inhibitor ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

TPS7062 Background: FLT3-ITD is one of the most common genetic lesions in acute myeloid leukemia (AML). PIM kinases are oncogenic FLT3-ITD targets expressed in AML cells and increased PIM kinase expression is found in relapse samples from AML patients treated with FLT3 inhibitors. In addition, inhibition of PIM kinases restores sensitivity to FLT3 inhibitors and dual FLT3/PIM inhibition eradicates FLT3-ITD+ cells including primary AML cells. SEL24/MEN1703, a potent PIM/FLT3 dual inhibitor, demonstrates a significantly broader spectrum of activity in AML cell lines and primary AML blasts, irrespective of FLT3 status, compared to monotherapy with either FLT3 or PIM inhibitors such as quizartinib or AZD1208. Methods: CLI24-001 is a First in Human, open label, non-randomized, multi-center, Phase I/II dose-escalation and cohort expansion study of SEL24/MEN1703 in AML patients (excluding APL) not suitable for chemotherapy. SEL24/MEN1703 is given orally, QD, for 14 days in a 21-day cycle with cycles repeated until disease progression or unacceptable toxicity. Dose escalation follows a 3+3 design to identify the recommended phase 2 dose (RP2D). In the phase 2 part/cohort expansion, subjects will receive SEL24/MEN1703 at the RP2D, to further investigate the safety profile and signs of antileukemic activity. In both study parts, patients are eligible regardless of mutational status and/or prior exposure to FLT3 inhibitors; prior treatment with PIM inhibitors is not allowed. Main inclusion criteria comprise a white blood count (WBC) of ≤30 x 109/L (hydroxyurea/leukoapheresis permitted to lower WBC). Key secondary objectives include pharmacokinetics (PK) and single agent efficacy. The study is enrolling at 5 US sites and will be extended, both in US and EU, in the cohort expansion part. This is the first trial testing a dual PIM/FLT3 inhibitor with the potential to be active in AML regardless of FLT3 status andwith a potential to overcome FLT3 inhibitor resistance. (Sci Adv. 2015;1:e1500221; Oncotarget. 2018 Mar 30;9(24):16917-16931) Clinical trial information: NCT03008187.

Selective FLT3 Inhibitor FI-700 Neutralizes Mcl-1 and Enhances p53-Mediated Apoptosis in Acute Myeloid Leukemia (AML) Cells with Activating Mutations of FLT3 Via Mcl-1/Noxa Axis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2597-2597
Author(s):  
Kensuke Kojima ◽  
Marina Konopleva ◽  
Twee Tsao ◽  
Michael Andreeff ◽  
Hiroshi Ishida ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Activating Mutations ◽  
Phosphatidylserine Externalization ◽  
Flt3 Inhibitor ◽  
Flt3 Mutations ◽  
Flt3 Inhibitors ◽  
Induced Apoptosis ◽  
Apoptotic Effects ◽  
Acute Myeloid

Abstract Abstract 2597 Poster Board II-573 Introduction: Activating mutations of the Fms-like tyrosine kinase-3 gene (FLT3) occur in approximately 30–40% of acute myeloid leukemia (AML) patients. FLT3 mutations confer numerous oncogenic properties, including dysregulated proliferation, resistance to apoptosis and a block in differentiation. FLT3 mutations result in abnormal activation of the downstream pathways, including signal transducer and activator of transcription 5 (STAT5), mitogen-activated protein kinase kinase (Mek)/extracellular signal–regulated kinase (Erk) and phosphatidylinositol-3 kinase (PI3K)/Akt. Activation of these downstream effectors has been thought to allow leukemia cells to evade apoptosis. Targeting of FLT3 mutations is a promising approach to overcome the dismal prognosis of acute myeloid leukemia (AML) with activating FLT3 mutations. Current trials are combining FLT3 inhibitors with p53-activating conventional chemotherapy. The mechanisms of cytotoxicity of FLT3 inhibitors are poorly understood. We investigated the interaction of FLT3 and p53 pathways after their simultaneous blockade using the selective FLT3 inhibitor FI-700 and the MDM2 inhibitor Nutlin-3 in AML. Results: FI-700 induced G1-phase cell cycle arrest and apoptosis as evidenced by increased sub-G1 DNA content and phosphatidylserine externalization in FLT3/ITD MOLM-13 (FLT3-ITD, wild-type (wt)-p53) and MV4-11NR (FLT3-ITD, mutated-p53) AML cells. FI-700 did not affect cell cycle distribution patterns nor did it induce apoptosis in FLT3/WT OCI-AML-3 (FLT3/WT, wt-p53) and HL-60 (FLT3/WT, del (del)-p53). Wt-p53 MOLM-13 and OCI-AML-3 cells were susceptible to Nutlin-induced apoptosis. FI-700 augmented Nutlin-induced Bax activation, mitochondrial membrane potential (MMP) loss, caspase-3 activation and phosphatidylserine externalization in MOLM-13 cells. FI-700 rapidly reduced Mcl-1 levels in FLT3/ITD cells, mainly by enhancing proteasomal Mcl-1 degradation. Levels of other Bcl-2 family proteins examined did not change significantly. Mcl-1 levels were only modestly reduced upon Nutlin treatment. The FI-700/Nutlin-3 combination profoundly reduced Mcl-1 levels. Immunoprecipitation/ immunoblotting results suggested that the drug combination results in a profound decrease in Mcl-1-bound Bim. FI-700 enhanced doxorubicin-induced apoptosis in FLT3/ITD MOLM-13 and MV4-11NR cells, suggesting that FI-700 can enhance both the p53-dependent and the p53-independent apoptotic effects of doxorubicin. Finally, cooperative apoptotic effects of FI-700/Nutlin-3 were seen in primary AML cells with FLT3/ITD. Conclusion: FLT3 inhibition by FI-700 immediately reduces anti-apoptotic Mcl-1 levels and enhances Nutlin-induced p53-mediated mitochondrial apoptosis in FLT3/ITD-expressing AML cells via the Mcl-1/Noxa axis. FLT3 inhibition, in combination with p53-inducing agents, might represent a potential therapeutic approach in AML with FLT3/ITD. Disclosures: No relevant conflicts of interest to declare.

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