General AML

The extracellular matrix of leukemic cells and AML- A Finnish study

The Extracellular Matrix (ECM) is a complex network of cross-linked proteins providing architectural support for cells and it is also an element of the tumor microenvironment. It has been proposed that Acute Myeloid Leukemia (AML) arises from the Leukemia Stem Cells (LSCs), which has been shown to alter elements of the ECM. The direct contribution of LSCs to the ECM niche has not been investigated yet, hence the rationale for this study.

In a Letter to the Editor of Haematologica, Valerio Izzi from the University of Oulu, Finland, and colleagues investigated the transcriptional profile of ECM-related genes in LSCs and their prognostic significance in AML patients.

Raw microarray profiles of normal Hematopoietic Stem Cells (HSCs), committed progenitors, Multipotent Progenitors (MPPs) and LSCs from the NCBI Gene Expression (GEO) repository were analyzed and validated in AML patient data from GEO (GSE10358) and The Cancer Genome Atlas (TCGA) AML Cohorts.

The key results of the study were:
  • Grouping of 80 ECM genes using Principal Component Analysis (PCA) or Ward’s method identified 3 clusters; one which contains only leukemic cells (definitive leukemic cells), one which contains committed precursors and one which contains a mix of HSCs and MPPs (early leukemic cells)
  • Patients with early leukemic cells had a significantly better Overall Survival (OS) compared to patients with definitive leukemic cells in both TCGA (P = 0.025) and GSE10358 (P = 0.039) cohort
  • Event Free Survival (EFS) and Disease Free Survival (DFS) were significantly better in patients with early leukemic cells than definitive leukemic cells in the GSE10358 (P = 0.041) and TCGA (P = 0.019) cohort respectively
  • Compared to early leukemic cells, CD44 (transmembrane glycoprotein) was significantly upregulated in definitive leukemic cells; P = 0.028

The authors highlighted that their study is the first to show “the existence of an ECM signature that is shared between leukemia precursor cells and circulating AML cells from patients”. Additionally, the authors added that “increased CD44 in definitive leukemic cells indicates a crucial step in the progression of leukemic cells towards an aggressive phenotype”.

Izzi et al., concluded by stating that “the correlation of the ECM signature with AML outcome and leukemic precursor subtypes suggests a central role for ECM alteration in AML biology and encourages further studies to understand the regulatory mechanisms controlling it”.

References
  1. Naba A. et al., The extracellular matrix: Tools and insights for the “omics” era. Matrix Biol. 2016 Jan; 49: 10–24. DOI: 10.1016/j.matbio.2015.06.003. Epub 2015 Jul 8.
  2. Izzi V. et al. An Extracellular Matrix Signature In Leukemia Precursor Cells And Acute Myeloid Leukemia. Haematologica. 2017 Apr 14. DOI: 10.3324/haematol.2017.167304. [Epub ahead of print].