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Single cell analysis exposes intra-tumor heterogeneity and suggests that FLT3-ITD is a late event in leukemogenesis

Authors
  • Shouval, Roni
  • Shlush, Liran I.
  • Yehudai-Resheff, Shlomit
  • Ali, Shahnaz
  • Pery, Neta
  • Shapiro, Ehud
  • Tzukerman, Maty
  • Rowe, Jacob M.
  • Zuckerman, Tsila1, 2, 3, 4, 5, 6, 7, 8
  • 1 Bruce Rappaport Faculty of Medicine and Research Institute
  • 2 Technion – Israel Institute of Technology
  • 3 Department of Biological Chemistry
  • 4 Weizmann Institute of Science
  • 5 Department of Hematology
  • 6 Shaare Zedek Medical Center
  • 7 Department of Hematology & Bone Marrow Transplantation
  • 8 Rambam Healthcare Campus
Type
Published Article
Journal
Experimental Hematology
Publisher
Elsevier
Publication Date
Jan 01, 2014
Accepted Date
Jan 27, 2014
Identifiers
DOI: 10.1016/j.exphem.2014.01.010
Source
Elsevier
Keywords
License
Unknown

Abstract

FMS-like tyrosine kinase 3 receptor- internal tandem duplication (FLT3-ITD) commonly occurs in acute myeloid leukemia (AML) and is considered rare in acute lymphocytic leukemia (ALL). Acute leukemia has poor prognosis, mainly due to relapse. Standard FLT3-ITD diagnostic techniques are based on genomic PCR and have recently incorporated GeneScan to identify variations of the FLT3 gene. As this is an average-based assay utilized in a heterogeneous leukemic cell population, we hypothesized that cells of acute leukemia, considered FLT3-ITD-negative by standard methods, could possess a fraction of FLT3-ITD-positive cells. The present study employed single cell mutation analysis to evaluate the FLT3-ITD status in newly diagnosed AML (n=5) and ALL (n=3) patients. A total of 541 single leukemic cells and 36 mononuclear cells from healthy volunteers were analyzed. 7/8 patients considered FLT3-ITD-negative according to bulk DNA analysis, appeared to possess a small fraction of FLT3-ITD-positive cells based on single cell analysis (SCA). Moreover, this approach revealed the heterogeneity of the tumor as evident by different FLT3-ITD mutations present in the same patient. The presence of a minor clone carrying FLT3-ITD in almost all patients tested, provides an evidence that this lesion is a common late event in leukemogenesis. Additionally, 3 relapsed patients demonstrated loss of heterozygosity (LOH) of the normal allele, affecting 25-100% of the cells found to be FLT3-ITD-positive. Though further clinical testing is warranted, these findings may have implications on the prognostic significance of FLT3-ITD and the use of targeted therapy.

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