Dasatinib response in acute myeloid leukemia is correlated with FLT3/ITD, PTPN11 mutations and a unique gene expression signature

Sigal Tavor, Tali Shalit, Noa Chapal Ilani, Yoni Moskovitz, Nir Livnat, Yoram Groner, Haim Barr, Mark D Minden, Alexander Plotnikov, Michael W Deininger, Nathali Kaushansky, Liran I Shlush

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)
103 Downloads (Pure)

Abstract

Novel targeted therapies demonstrate improved survival in specific subgroups (defined by genetic variants) of acute myeloid leukemia (AML) patients, validating the paradigm of molecularly targeted therapy. However, identifying correlations between AML molecular attributes and effective therapies is challenging. Recent advances in high-throughput in vitro drug sensitivity screening applied to primary AML blasts were used to uncover such correlations; however, these methods cannot predict the response of leukemic stem cells (LSCs). Our study aimed to predict in vitro response to targeted therapies, based on molecular markers, with subsequent validation in LSCs. We performed ex vivo sensitivity screening to 46 drugs on 29 primary AML samples at diagnosis or relapse. Using unsupervised hierarchical clustering analysis we identified group with sensitivity to several tyrosine kinase inhibitors (TKIs), including the multi-TKI, dasatinib, and searched for correlations between dasatinib response, exome sequencing and gene expression from our dataset and from the Beat AML dataset. Unsupervised hierarchical clustering analysis of gene expression resulted in clustering of dasatinib responders and non-responders. In vitro response to dasatinib could be predicted based on gene expression (AUC=0.78). Furthermore, mutations in FLT3/ITD and PTPN11 were enriched in the dasatinib sensitive samples as opposed to mutations in TP53 which were enriched in resistant samples. Based on these results, we selected FLT3/ITD AML samples and injected them to NSG-SGM3 mice. Our results demonstrate that in a subgroup of FLT3/ITD AML (4 out of 9) dasatinib significantly inhibits LSC engraftment. In summary we show that dasatinib has an anti-leukemic effect both on bulk blasts and, more importantly, LSCs from a subset of AML patients that can be identified based on mutational and expression profiles. Our data provide a rational basis for clinical trials of dasatinib in a molecularly selected subset of AML patients.
Original languageEnglish
Pages (from-to)2795-2804
Number of pages10
JournalHaematologica
Volume105
Issue number12
Early online date7 May 2020
DOIs
Publication statusPublished - Dec 2020

Funding

This research was supported by a grant from the Nancy and Stephen Grand Israel National Center for Personalized Medicine to HB and by the EU horizon 2020 grant project MAMLE ID: 714731, LLS grant ID: RTF6005-19, and IMOS-712843 awarded to LIS. LIS is an incumbent of the Ruth and Louis Leland career development chair. NK is an incumbent of the Applebaum Foundation Research Fellow Chair. This research was also supported by the Sagol Institute for Longevity Research, the Barry and Eleanore Reznik Family Cancer Research Fund, Steven B. Rubenstein Research Fund for Leukemia and Other Blood Disorders, the Rising Tide Foundation and the Applebaum Foundation.

Fingerprint

Dive into the research topics of 'Dasatinib response in acute myeloid leukemia is correlated with FLT3/ITD, PTPN11 mutations and a unique gene expression signature'. Together they form a unique fingerprint.

Cite this