Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia

Abstract

The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.

Donor cell leukemia: insight into cancer stem cells and the stem cell niche

“…44 In BCR-ABL-associated leukemias, the transformation occurs at the stem cell and progenitor cell level depending on the phenotype and fusion transcript isoform. 45 Several other exceptions exist, including PML-RAR␣, 46 MLL-ENL, 47 and MOZ-TIF2, 48 whereby leukemia is promoted by fusion oncogenes, and self-renewal characteristics are imposed on more committed progenitors in the hematopoietic hierarchy. These models suggest an intrinsic cellular mechanism for leukemogenesis.…”

Epigenetics and the plasticity of differentiation in normal and cancer stem cells

“…It has recently been emphasized that cancer therapy should include the targeting of cancer stem cells (Singh et al, 2003;Valk-Lingbeek et al, 2004;Behbod and Rosen, 2005;Bjerkvig et al, 2005;Bonnet, 2005). Although cancer cells can be derived from normal self-renewing stem cells, more differentiated normal cells can also give rise to tumors (Cozzio et al, 2003;Castor et al, 2005). Experiments with mature brain astrocytes have shown that combined loss of the tumor suppressor genes p16 Ink4 and p19 Arf and constitutive activation of the EGF receptor caused a loss of differentiation.…”

Leukemia-associated genetic aberrations in mesenchymal stem cells of children with acute lymphoblastic leukemia

“…The leukemia-associated genetic aberrations were less frequent in MSC than reported for HSC and leukemia cells from ALL patients (170). …”