Gene expression profiling of acute promyelocytic leukaemia identifies two subtypes mainly associated with Flt3 mutational status

Abstract

Acute promyelocytic leukaemia (APL) is a well-defined disease characterized by a typical morphology of leukaemic cells, the presence of t(15;17) translocation and the unique sensitivity to the differentiating effect of all-trans retinoic acid. Nevertheless, some aspects are variable among APL patients, with differences substantially related to morphological variants, peripheral leukocytes count, the presence of a disseminated intravascular coagulopathy, different PML/RARa isoforms (long, variable or short) and Fms-like tyrosine kinase 3 (Flt3) mutations. In order to better define this variability, we investigated the gene expression profiles of 18 APL cases revealing, besides a high uniformity in gene expression pattern, the presence of few robust differences among patients able to identify, by an unsupervised analysis, two major clusters of patients characterized by different phenotypes (hypogranular M3v vs classical M3) and by the presence or absence of Flt3 internal tandem duplications (ITDs). Further supervised analysis confirmed that Flt3 status was the APL parameter best associated with these two subgroups. We identified, between Flt3 wild-type and Flt3-ITDs subsets, 147 differentially expressed genes that were involved in the cytoskeleton organization, in the cell adhesion and migration, in the proliferation and the coagulation/inflammation pathways as well as in differentiation and myeloid granules constitution suggesting a role of Flt3 mutations in the pathogenesis and clinical manifestations of APL.

Occurrence of thrombotic events in acute promyelocytic leukemia correlates with consistent immunophenotypic and molecular features

“…29,30 FLT-ITD is recognized as an adverse factor for response to therapy and outcome in AML, 31,32 although its prognostic significance in APL is less clear. As to the biological role of this genetic alteration, it is known that FLT-ITD leads to constitutive activation of the receptor resulting in increased proliferation of leukemic cells.…”

The Biology of Acute Promyelocytic Leukemia and Its Impact on Diagnosis and Treatment

“…[30][31] In addition, microarray analysis revealed differences in expression profiles between patients with mutated and wild-type FLT3, with patients in the former group showing increased expression of genes involved in cell growth, cell cycle control, cell adhesion and migration, and the coagulation/inflammation pathway. 31,32 Together, these studies suggest a role of FLT3 mutations in the pathogenesis and clinical manifestations of APL. Combined with the results of studies in transgenic mice for both PML/RARα and FLT3 33 these data also suggest that FLT3 mutations are most likely associated with disease progression.…”

Angiopoietin-2 expression in B-cell chronic lymphocytic leukemia: association with clinical outcome and immunoglobulin heavy-chain mutational status

“…Exploratory experiments of gene expression profiling (GEP) were previously performed in our laboratory on 29 unpurified CLL samples (% CD5 þ CD19 þ cells, 8279%) (data deposited in NCBIs Gene Expression Omnibus http://www.ncbi.nlm.nih.gov/ geo/, Accession:GSE4207) with Agilent Human-1A-OligoMicroarray comprising 20 173 (60-mer) oligonucleotide probes using the protocol described elsewhere. 6 Among the differentially expressed genes between 14 Ig-mutated CLL (M-CLL) and 15 Ig-unmutated CLL (UM-CLL) subsets, Ang-2 was found as one of the most up-regulated genes in UM-CLL relative to M-CLL (P ¼ 3.02 Â 10 À6 , ANOVA). These results prompted us to undertake a survey of our own CLL patients to examine further the relationship between Ang-2 expression, immunoglobulin (Ig) mutational status and other established prognostic markers as well as progression-free survival.…”