Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.
Announcing new Tapestri Platform updates including lowered input threshold and expanded heme-onc menu. Learn More

Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia

Wang, F. et al.
Nature Communications (2021)

Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RASRTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.


Wang, F., Morita, K., DiNardo, C.D., Furudate, K., Tanaka,T., Yan, Y., Patel, K.P., MacBeth, K.J., Wu, B., Liu, G., Frattini, M., Matthews, J.A., Little, L.D., Gumbs, C., Song, X., Zhang, J., Thompson, E.J., Kadia, T.M., Garcia-Manero, G., Jabbour, E., Ravandi, F., Bhalla, K.N., Konopleva, M., Kantarjian, H.M., Futreal, P.A., Takahashi, K.


Molecular characterization of acquired resistance to KRAS G12C inhibition in gastrointestinal cancers
Misale S
Research Square (2022)
Preneoplastic somatic mutations including MYD88L265P in lymphoplasmacytic lymphoma
Rodriguez S
Science Advances (2022)
Single-cell sequencing demonstrates complex resistance landscape in CLL and MCL treated with BTK and BCL2 inhibitors
Thompson ER
Blood Advances (2021)
Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue
Sharma R
Blood (2021)