Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Acute myeloid leukemia

Notch blockade overcomes endothelial cell-mediated resistance of FLT3/ITD-positive AML progenitors to AC220 treatment

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: EC coculture improved survival of FLT3/ITD-positive progenitors treated with AC220.
Fig. 2: Inhibiting Notch signaling reduced EC-mediated protection of FLT3/ITD-positive CFCs in the presence of AC220 for patient samples with high FLT3-AR.

Data availability

RNA-seq data are available at GEO, accession GSE138340.


  1. 1.

    Pollard JA, Alonzo TA, Gerbing RB, Woods WG, Lange BJ, Sweetser DA, et al. FLT3 internal tandem duplication in CD34+/CD33- precursors predicts poor outcome in acute myeloid leukemia. Blood. 2006;108:2764–9.

    CAS  Article  Google Scholar 

  2. 2.

    Yang X, Sexauer A, Levis M. Bone marrow stroma-mediated resistance to FLT3 inhibitors in FLT3-ITD AML is mediated by persistent activation of extracellular regulated kinase. Br J Haematol. 2014;164:61–72.

    CAS  Article  Google Scholar 

  3. 3.

    Poulos MG, Gars EJ, Gutkin MC, Kloss CC, Ginsberg M, Scandura JM, et al. Activation of the vascular niche supports leukemic progression and resistance to chemotherapy. Exp Hematol. 2014;42:976–86.e1-3.

    CAS  Article  Google Scholar 

  4. 4.

    Ghajar CM. Metastasis prevention by targeting the dormant niche. Nat Rev Cancer. 2015;15:238–47.

    CAS  Article  Google Scholar 

  5. 5.

    Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, et al. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell. 2010;6:251–64.

    CAS  Article  Google Scholar 

  6. 6.

    Walter RB, Laszlo GS, Lionberger JM, Pollard JA, Harrington KH, Gudgeon CJ, et al. Heterogeneity of clonal expansion and maturation-linked mutation acquisition in hematopoietic progenitors in human acute myeloid leukemia. Leukemia. 2014;28:1969–77.

    CAS  Article  Google Scholar 

  7. 7.

    Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP, Chen Y, et al. Therapeutic antibody targeting of individual Notch receptors. Nature. 2010;464:1052–7.

    CAS  Article  Google Scholar 

  8. 8.

    Wang W, Yu S, Zimmerman G, Wang Y, Myers J, Yu VW, et al. Notch receptor-ligand engagement maintains hematopoietic stem cell quiescence and niche retention. Stem Cells. 2015;33:2280–93.

    CAS  Article  Google Scholar 

  9. 9.

    Catelain C, Michelet F, Hattabi A, Poirault-Chassac S, Kortulewski T, Tronik-Le Roux D, et al. The Notch delta-4 ligand helps to maintain the quiescence and the short-term reconstitutive potential of haematopoietic progenitor cells through activation of a key gene network. Stem Cell Res. 2014;13:431–41.

    CAS  Article  Google Scholar 

  10. 10.

    Wang W, Yu S, Myers J, Wang Y, Xin WW, Albakri M, et al. Notch2 blockade enhances hematopoietic stem cell mobilization and homing. Haematologica. 2017;102:1785–95.

    CAS  Article  Google Scholar 

  11. 11.

    Takam Kamga P, Bassi G, Cassaro A, Midolo M, Di Trapani M, Gatti A, et al. Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia. Oncotarget. 2016;7:21713–27.

    Article  Google Scholar 

  12. 12.

    Liau BB, Sievers C, Donohue LK, Gillespie SM, Flavahan WA, Miller TE, et al. Adaptive chromatin remodeling drives glioblastoma stem cell plasticity and drug tolerance. Cell Stem Cell. 2017;20:233–46.e7.

    CAS  Article  Google Scholar 

  13. 13.

    Weerkamp F, Luis TC, Naber BA, Koster EE, Jeannotte L, van Dongen JJ, et al. Identification of Notch target genes in uncommitted T-cell progenitors: no direct induction of a T-cell specific gene program. Leukemia. 2006;20:1967–77.

    CAS  Article  Google Scholar 

  14. 14.

    Lobry C, Ntziachristos P, Ndiaye-Lobry D, Oh P, Cimmino L, Zhu N, et al. Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J Exp Med. 2013;210:301–19.

    CAS  Article  Google Scholar 

  15. 15.

    Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–35.

    CAS  Article  Google Scholar 

Download references


This study was supported by The Hartwell Fellowship Foundation to QL. We thank Chris Siebel (Genentech) for the anti-NRR1 and anti-NRR2 antibodies and Shahin Rafii (Weill Cornell Medical College) for the E4ORF1 lentivirus construct.

Author information




QL and IB designed the experiments; QL performed the experiments and analyzed the data; QL, IB, BH, and SM wrote the paper.

Corresponding author

Correspondence to Irwin Bernstein.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Le, Q., Hadland, B., Meshinchi, S. et al. Notch blockade overcomes endothelial cell-mediated resistance of FLT3/ITD-positive AML progenitors to AC220 treatment. Leukemia 35, 601–605 (2021).

Download citation


Quick links