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

Authors
  • Shouval, Roni1
  • Shlush, Liran I2
  • Yehudai-Resheff, Shlomit3
  • Ali, Shahnaz1
  • Pery, Neta1
  • Shapiro, Ehud2
  • Tzukerman, Maty1
  • Rowe, Jacob M4
  • Zuckerman, Tsila5
  • 1 Bruce Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel. , (Israel)
  • 2 Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel. , (Israel)
  • 3 Department of Hematology & Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel. , (Israel)
  • 4 Bruce Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel; Department of Hematology & Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel; Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel. , (Israel)
  • 5 Bruce Rappaport Faculty of Medicine and Research Institute, Technion - Israel Institute of Technology, Haifa, Israel; Department of Hematology & Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel. Electronic address: [email protected] , (Israel)
Type
Published Article
Journal
Experimental hematology
Publication Date
Jun 01, 2014
Volume
42
Issue
6
Pages
457–463
Identifiers
DOI: 10.1016/j.exphem.2014.01.010
PMID: 24495871
Source
Medline
License
Unknown

Abstract

FMS-like tyrosine kinase 3 receptor-internal tandem duplication (FLT3-ITD) commonly occurs in acute myeloid leukemia and is considered rare in acute lymphocytic leukemia. Acute leukemia has poor prognosis, mainly due to relapse. Standard FLT3-ITD diagnostic techniques are based on genomic polymerase chain reaction and have recently incorporated GeneScan (Applied Biosystems, Foster City, CA) 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 acute myeloid leukemia (n = 5) and acute lymphocytic leukemia (n = 3) patients. A total of 541 single leukemic cells and 36 mononuclear cells from healthy volunteers were analyzed. Seven 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. 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 evidence that this lesion is a common late event in leukemogenesis. Additionally, 3 relapsed patients demonstrated loss of heterozygosity 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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