Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Sep;35(9):2698-2702.
doi: 10.1038/s41375-021-01273-7. Epub 2021 May 17.

SF3B1 as therapeutic target in FLT3/ITD positive acute myeloid leukemia

Inge van der Werf  1 , Anna Wojtuszkiewicz  2 , Huilan Yao  3 , Rocco Sciarrillo  2 , Manja Meggendorfer  4 , Stephan Hutter  4 , Wencke Walter  4 , Jeroen Janssen  2 , Wolfgang Kern  3 , Claudia Haferlach  3 , Torsten Haferlach  3 , Gerrit Jansen  5 , Gertjan J L Kaspers  6   7 , Richard Groen  2 , Gert Ossenkoppele  2 , Jacqueline Cloos  2
Affiliations

SF3B1 as therapeutic target in FLT3/ITD positive acute myeloid leukemia

Inge van der Werf et al. Leukemia. 2021 Sep.

Erratum in

No abstract available

PubMed Disclaimer

Conflict of interest statement

TH, CH and WK are part owners of MLL; MM, SH and WW are employed by MLL.

Figures

Fig. 1
Fig. 1. Response of primary AML cells with or without FLT3/ITD to splicing modulation.
Ex vivo AML patients’ cells taken at diagnosis were selected based on their FLT3 mutation status and the absence of any other aberrations based on our diagnostic panel. Light blue dots (−) represent FLT3/ITDneg samples whereas dark blue dots (+) represent FLT3/ITDpos specimens. A, B Cells were treated for 48 h with indicated doses of E7107. Cell count of the total white blood cell populations (WBC) was determined using Flow Cytometry. Progenitors were identified based on CD34 expression. Cell counts are depicted as percentage of untreated cells. C Clonogenic capacity of FLT3/ITDpos cells derived from a primary bone marrow sample upon treatment with E7107 or H3B-8800. P values are based on Kruskas Wallis test. D Cells were treated for 48 h with indicated doses of Bortezomib. Cell count of the total white blood cell populations (WBC) was determined using Flow Cytometry. Cell counts are depicted as percentage of untreated cells. P values are based on Mann–Whitney U test. E Schematic of the effect of splicing modulation on both pre-mRNA as well as mature mRNA levels presented in (G). In short, splicing modulation via E7107 or H3B-8800 results in decreased production of mature mRNA transcripts (mat; blue) and concomitant accumulation of pre-mRNA transcripts (pre; red). In addition, alternative junctions (AJ; red) of certain genes are preferred upon splicing modulation resulting in decreased expression of constitutive spliced mRNAs (CJ; blue). (F) Representative heatmap of 3 patients samples depicting dose-dependent modulation for both mature as well as pre-mature mRNA markers in FLT3/ITDneg (left) and FLT3/ITDpos (right) cells. (G) Correlation between the response of AML patients’ cells to 10 nM E7107 or 250 nM H3B-8800. A strong association between both splicing modulators as indicated by high Spearman’s rho correlation coefficient (R).
Fig. 2
Fig. 2. Preferential sensitivity to splicing modulation of FLT3/ITDpos AML patients with high AR or long ITD length.
A Cell counts of CD34 positive cells within bone marrows of patient samples grouped based on their FLT3/ITD allelic ratio according to the ELN 2017 following treatment with 10 nM E7107. B Cell counts of CD34 positive cells within bone marrows of patient samples grouped on their ITD size. Cut off was based on mean size of ITD length of selected patients. C Cell count of the total white blood cell population within healthy bone marrow was assessed upon treatment. D Cell counts of lymphocytes within AML bone marrow samples were identified based on CD45, CD34, and CD7 expression. E Cell counts of CD34 positive cells within healthy bone marrow samples was determined upon treatment with 10 nM E7107 for 48 h. Cell counts were plotted as a percentage of untreated cells. The Mann–Whitney U test was used to compare response levels between different groups of patients or normal bone marrow.
See this image and copyright information in PMC

References

    1. Lee SC-W, Abdel-Wahab O. Therapeutic targeting of splicing in cancer. Nat Med. 2016;22:976–86. doi: 10.1038/nm.4165. - DOI - PMC - PubMed
    1. Buonamici S, Yoshimi A, Thomas M, Seiler M, Chan B. Caleb B, et al. H3B-8800, an orally bioavailable modulator of the SF3b complex, shows efficacy in spliceosome-mutant myeloid malignancies. Blood. 2016;128:966–966. doi: 10.1182/blood.V128.22.966.966. - DOI
    1. Seiler M, Yoshimi A, Darman R, Chan B, Keaney G, Thomas M, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018;24:497–504. doi: 10.1038/nm.4493. - DOI - PMC - PubMed
    1. Adamia S, Haibe-Kains B, Pilarski PM, Bar-Natan M, Pevzner S, Avet-Loiseau H, et al. A genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets. Clin Cancer Res. 2014;20:1135–45. doi: 10.1158/1078-0432.CCR-13-0956. - DOI - PMC - PubMed
    1. Stirewalt DL, Radich JP. The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer. 2003;3:650–65. doi: 10.1038/nrc1169. - DOI - PubMed

Publication types

MeSH terms

LinkOut - more resources