Initiating and Cancer-Propagating Cells in TEL-AML1 -Associated Childhood Leukemia

Abstract

Understanding cancer pathogenesis requires knowledge of not only the specific contributory genetic mutations but also the cellular framework in which they arise and function. Here we explore the clonal evolution of a form of childhood precursor-B cell acute lymphoblastic leukemia that is characterized by a chromosomal translocation generating a TEL-AML1 fusion gene. We identify a cell compartment in leukemic children that can propagate leukemia when transplanted in mice. By studying a monochorionic twin pair, one preleukemic and one with frank leukemia, we establish the lineal relationship between these "cancer-propagating" cells and the preleukemic cell in which the TEL-AML1 fusion first arises or has functional impact. Analysis of TEL-AML1-transduced cord blood cells suggests that TEL-AML1 functions as a first-hit mutation by endowing this preleukemic cell with altered self-renewal and survival properties.

Molecular Genetic Studies on 167 Pediatric ALL Patients from Different Areas of Pakistan Confirm a Low Frequency of the Favorable Prognosis Fusion Oncogene TEL-AML1 (t 12; 21) in Underdeveloped Countries of the Region

“…In several studies, the application of molecular and cytogenetic tools such as fluorescent in situ hybridization (FISH), southern blot analysis, karyotyping and RT-PCR have shown TEL-AML1 fusion transcripts in up to 20-30% of childhood ALL, making it the most common molecular cytogenetic abnormality in pediatric ALL (Lewis, 2007;Hong et al, 2008). TEL and AML-I genes involved in this translocation play important role in the pathogenesis of human leukemia (Woerden et al, 2000;Tsuzuki and Seto, 2013).…”

Cancer cells in epithelial-to-mesenchymal transition and tumor-propagating–cancer stem cells: distinct, overlapping or same populations

“…Independently of the possible origin of CSC in somatic stem cells (Alison et al, 2010), the use of this denomination implies some explicit but also implicit assumptions, varying from one author to another, that we and others have previously analyzed (Shackleton et al, 2009;Dirks, 2010;Maenhaut et al, 2010;Roesch et al, 2010;Shackleton, 2010). To avoid misconceptions, we and others have proposed to call such cells 'tumor-propagating cells' (TPCs) in agreement with their operational demonstration by xenografts (Kelly et al, 2007;Hong et al, 2008;Maenhaut et al, 2010). In this review, we shall use the term CSC-TPC to designate these cells except when citing authors who emphasized the 'CSC' denomination when describing their findings.…”

“…We do not use the term CSC-tumorinitiating cell, as this term (Mani et al, 2008) could lead to a confusion with the cells in which the cancer was initiated in vivo. The highly productive concept of CSC-TPC (Lapidot et al, 1994;Clarke and Fuller, 2006;Kelly et al, 2007;Hong et al, 2008;Alison et al, 2011) has represented a major advance in cancer research.…”

Deciphering the Key Features of Malignant Tumor Microenvironment for Anti-cancer Therapy

“…At the initial stage of tumorigenesis, intrinsic and extrinsic factors cause intracellular genetic mutations and epigenetic alterations, resulting in generation of oncogenes that induce the production of CSCs and tumorigenesis [6]. The CSCs can be produced from precancerous stem cells [59][60][61][62][63][64], cell de-differentiation [65], or an epithelial-mesenchymal transition [66][67][68]. Malignant mesenchymal stem cells have been found in the niche of cancers [66,67], and an epithelial-mesenchymal transition may be an early key step in the initiation of TME and tumorigenesis [68].…”

“…3). These tumor cells include precancerous stem cells [59][60][61], CSCs [62][63][64], and vasculogenic tumor cells [71][72][73][74][75].…”