Abstract 824P
Background
FLT3-ITD is one of the most common genetic abnormalities in acute myeloid leukemia (AML) and suggests a poor prognosis. The impact of FLT3-ITD on the immune microenvirenment requires further elucidation. Studies have shown that FLT3-ITD can significantly change the level of immune cells in the bone marrow in mice.
Methods
Flow cytometry was used to detect the CD47 mean fluorescent intensity (MFI). The FLT3 wildtype (FLT3-OE, FLT3 over expression) or ITD mutation (FLT3-ITD) stable overexpression K562/HEL cells were constructed by lentiviral transfections. The TRANSFAC database was used to predict the transcription factor binding sites of the CD47 promoter. We analyzed the location of CD47 gene on the chromosome, the sequence of promoter and first non-coding exon of HOXB5 via Jaspar online tool. The AML mouse model was constructed by injection of FLT3-ITD cells.
Results
LDH-induced macrophage killing was less in FLT3-ITD cell lines than FLT3-WT cell lines. Expression of CD47 can help protect tumor cells from attack by macrophages. The CD47 MFI of the FLT3-ITD group was higher than that of the control group. The CD47 MFI of the FLT3-ITD group was significantly higher than that of FLT3-OE group and FLT3 normal control (FLT3-NC) group. Flow cytometry results showed that FLT3-ITD impaired the activity of red-stained macrophages to phagocytizing green-stained K652/HEL cells. Using the TRANSFAC database, we found higher relative expression of CD47 gene in FLT3-ITD group than other groups and that HOXB5 may regulate the expression of CD47 at transcriptional level. Integrated analysis of Jasper online tool, dual luciferase reporter gene assay and ChIP experiment suggest that HOXB5 directly activate CD47. Compared with other groups, combination of CD47 inhibitor and FLT3-ITD inhibitor Quizartinib (AC220) significantly enhanced phagocytic activity of macrophages. The mouse model of AML further showed that combination of CD47 inhibitor and Quizartinib significantly reduced tumor burden in spleen and bone marrow.
Conclusions
Our data show that FLT3-ITD can induce immune escape to macrophages by upregulating CD47. Combination therapy with CD47 inhibitor and FLT3-ITD inhibitor can be promising for the treatment of FLT3-ITD AML.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Sun Yat-sen University Start-Up Funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
826P - Efficacy of non-doxorubicin based regimens in severely G6PD deficient patients with DLBCL
Presenter: Shruti Prem Sudha
Session: Poster session 09
827P - Comparison of efficacy and safety between glofitamab and real-world regimens among Chinese patients with 3L+ relapsed/refractory diffuse large B-cell lymphoma: An external control study
Presenter: Keshu Zhou
Session: Poster session 09
828P - Translocation 11;14 is not associated with adverse prognosis in the era of novel anti-myeloma therapeutics
Presenter: Ioannis Ntanasis-Stathopoulos
Session: Poster session 09
829P - Flumatinib combined with chemotherapy for newly diagnosed adult with Ph-positive acute lymphoblastic leukemia: A single-center, retrospective observational study
Presenter: HAN SHUYU
Session: Poster session 09
830P - Prognostic model of pediatric AML patients with RUNX1-RUNX1T1 fusion gene
Presenter: Yang Xun
Session: Poster session 09
Resources:
Abstract
831P - Impact of chronic kidney disease on disease outcomes in hospitalized multiple myeloma patients: A National inpatient sample study from 2016 to 2020
Presenter: Marco Bermudez
Session: Poster session 09
Resources:
Abstract
832P - CLOMB: A validated scoring model to predict the relapse in the central nervous system of pediatric acute B-cell lymphoblastic leukemia
Presenter: Jiacheng Li
Session: Poster session 09
Resources:
Abstract
833P - Latest results of GVM±R regimen for the salvage therapy of patients with relapsed or refractory aggressive non-Hodgkin's lymphoma
Presenter: Wei Liu
Session: Poster session 09
834P - Treatment of DLBCL in HIV patient: Still a dilemma
Presenter: Devashish Desai
Session: Poster session 09
835P - Genetic, epigenetic, and clinical significance of Wilms’ tumor 1 (WT1) gene in acute myeloid leukemia
Presenter: Harsh Goel
Session: Poster session 09
Resources:
Abstract