Phenotypic and gene expression diversity of malignant cells in human blast crisis chronic myeloid leukemia

Masha Simanovsky, Sagi Berlinsky, Pirchia Sinai, Merav Leiba, Arnon Nagler, Hanan Galski

Research output: Contribution to journalArticlepeer-review

Abstract

Chronic myeloid leukemia (CML) is considered as a paradigm of neoplasias developing through multistep track. It is believed that in the blast crisis (BC) terminal phase of the disease, blood-circulating blasts represent an expansion of a single CML clone. However, although these blasts grow mostly in suspension under standard culture conditions, a relatively small cell-fraction adheres to the plastic dish. Yet, it is unknown whether these two cell-fractions are distinct sub-populations that originated from a common CML clone and whether they have different biological and malignant properties. To address these questions, we have characterized the plastic-adherent and non-adherent sub-populations of various cell lines and primary cells derived from patients with CML in BC. This study indicated that the adherent-subsets retain repopulating ability with indications of increased malignant properties as greater anchorage-independent clonogenicity, impairment of cell-cell contact inhibition, loss of serum-dependent attenuation of plastic-adhesion, and a significant up-regulation of the oncogenes BCR-ABL, c-JUN, and c-FOS along with the adhesion-related genes KiSS-1, THBS3, and ITGB5. The adherent blasts stably retain their unique properties even after elimination of the adherence selection pressure. Sub-cloning analyses indicated that the adherent cells could be continuously evolved from any parental non-adherent clone in a unidirectional manner. This study provides new insights into the biology and the malignant evolution of CML, indicating that at the BC phase, circulating blasts are heterogeneous and consisting of at least two distinct populations of a common clonal origin. The existence of a minor "pool" of blasts of greater clonogenic capacity along with significantly higher expression level of BCR-ABL, individually or in conjunction with other cancer and adhesion-related genes, might also signify clonal evolution toward subsequent increased malignancy and lower therapeutic sensitivity.

Original languageEnglish
Pages (from-to)908-922
Number of pages15
JournalDifferentiation
Volume76
Issue number8
DOIs
StatePublished - Oct 2008
Externally publishedYes

Keywords

  • Blast crisis
  • Chronic myeloid leukemia
  • Clonogenicity
  • Gene expression
  • Malignant evolution
  • Myeloblasts
  • Plastic adherence

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