FLT3,   General AML

FLT3/ITD are present in Leukemic Stem Cells (LSCs) and may be a primary event in the leukemogenesis

Adhra Al-Mawali, et al. analyzed thirty-four AML patients for the expression of CD123 in order to ascertain whether FMS-like tyrosine kinase (FLT3)/ Internal Tandem Duplication (ITD) mutations were present in both the total blast population and at stem cell level as defined by CD34+/CD38−. This analysis is of interest as the findings could provide the first conclusive data that FLT3/ITD mutations occur at the Leukemic Stem Cell (LSC) level and potentially provide further understanding on the development of leukemia. The results were published in J Hematol Oncol in 2016.

The key findings were:
  • 28/32 primary specimens demonstrated that CD123 was highly expressed in the CD34+/CD38− cells (96 ± 2% positive)
  • In 32/34 cases, there was significant expression of CD123 in the total blast population (median expression = 86%)
  • CD123 was not expressed/low in normal bone marrow CD34+/CD38− cells (median expression = 0%, range [0–.004%]) 

In conclusion, the presence of FLT3/ITD mutations has been demonstrated to occur at the LSC level. The oncogenic effects of FLT3/ITD mutation appear to take place at an early development stage. The targeting of CD123/IL-3α receptor may provide a novel mode of treatment in patients with CD123+ AML.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder presenting with accumulation of proliferating undifferentiated blasts. Xenograft transplantation studies have demonstrated a rare population of leukemia-initiating cells called leukemic stem cells (LSCs) capable of propagating leukemia that are enriched in the CD34+/CD38− fraction. LSCs are quiescent, resistant to chemotherapy and likely responsible for relapse and therefore represent an ideal target for effective therapy. LSCs are reported to overexpress the alpha subunit of the IL-3 receptor (CD123) compared to normal CD34+/CD38− hematopoietic stem cells. It has not been demonstrated whether CD123-positive (CD34+/CD38−) subpopulation is enriched for any clonal markers of AML or any LSC properties. The aims of this study were to investigate whether FMS-like tyrosine kinase (FLT3)/internal tandem duplication (ITD) mutations are present at LSC level and whether FLT3/ITD mutation is confined to LSC as defined by CD34+/CD38−/CD123+ and not CD34+/CD38−/CD123−.

References
  1. Al-Mawali A, et al. Immunoprofiling of leukemic stem cells CD34+/CD38−/CD123+ delineate FLT3/ITD-positive clones. Journal of Hematology and Oncology. 2016 July 27,9:61. DOI: 10.1186/s13045-016-0292-z.