Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors

Abstract

We have used the hematopoietic system as a model to investigate whether acute myeloid leukemia arises exclusively from self-renewing stem cells or also from short-lived myeloid progenitors. When transduced with a leukemogenic MLL fusion gene, prospectively isolated stem cells and myeloid progenitor populations with granulocyte/macrophage differentiation potential are efficiently immortalized in vitro and result in the rapid onset of acute myeloid leukemia with similar latencies following transplantation in vivo. Regardless of initiating cell, leukemias displayed immunophenotypes and gene expression profiles characteristic of maturation arrest at an identical late stage of myelomonocytic differentiation, putatively a monopotent monocytic progenitor stage. Our findings unequivocally establish the ability of transient repopulating progenitors to initiate myeloid leukemias in response to an MLL oncogene, and support the existence of cancer stem cells that do not necessarily overlap with multipotent stem cells of the tissue of origin. Received August 13, 2003; revised version accepted November 6, 2003. Hematopoiesis takes place through the stepwise differentiation of multipotent stem cells to generate a hierarchy of progenitor populations with progressively restricted developmental potential, ultimately leading to the production of multiple lineages of mature effector cells (Morrison and Weissman 1994;Akashi et al. 2000;Orkin 2000). Importantly, long-term self-renewal is normally limited to long-term hematopoietic stem cells (HSC) in the hematopoietic stem and progenitor pool (for review, see Weissman et al. 2001). A unifying feature of all cancers is the capacity for unlimited self-renewal, which is also a defining characteristic of normal stem cells (for review, see Reya et al. 2001). Given these shared attributes, it has been proposed that human cancer may be initiated by transforming events that take place in rare tissue-specific stem cells. Alternatively, cancers may arise from more committed progenitors due to mutations and/or selective gene expression that enhance their otherwise limited self-renewal capabilities (for review, see Passegué et al. 2003).Many of the transcription factors that control normal hematopoietic differentiation and proliferation are also targets for mutations associated with the development of acute leukemias (for review, see Tenen et al. 1997;Park et al. 2002), malignant diseases characterized by unregulated self-renewal. The MLL protein represents one such transcriptional regulator that is required for normal hematopoiesis (Hess et al. 1997;Yagi et al. 1998) and implicated in the maintenance of Hox gene expression (Breen and Harte 1993;Yu et al. 1995;Ayton and Cleary 2003), which is intimately tied to stem/progenitor cell expansion (Sauvageau et al. 1995;Lawrence et al. 1996). MLL fusion proteins, created by chromosomal translocation events, are frequently associated with the development of acute myeloid and lymphoid leukemias, and the oncogenic properties of a variety of MLL fusio...

Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia

“…Since these LSC -particularly in their dormant stage -may survive treatment and give rise to subsequent relapse [19,[28][29][30][31][32][33][34][35][36][37][38][39]. The latter idea is supported by a recent study showing that a higher level of putative CD34 + /CD38 --LSC is associated with a worse prognosis [40].…”

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…The association of MLL rearrangements with various hematopoietic lineages and the requirement of HOX expression in early development of hematopoietic cells suggest that MLL rearrangements occur in an early progenitor with lymphoid and myeloid potential. Although differences in translocation partner between AML and ALL suggest a role for lineage commitment, MLL-MLLT1(ENL) consistently generated AML in mice, 33 whereas MLL-MLLT1 is found in both AML and ALL in humans. MLL-GAS7 induced AML, ALL and acute biphenotypic leukemia in mice, 34 indicating that it is conceivable that, in addition to the MLL fusion, a secondary event or a specific microenvironment is necessary for lineage commitment.…”

Epigenetic regulation of aging stem cells

“…For example, in chronic myeloid leukemia, rare populations of self-renewing leukemia clones have similar expression profiles and markers of normal HSCs (Krivtsov et al, 2006). In other hematopoietic malignancies, an initiating lesion in self-renewing stem cells may progress to malignancy when coupled with increased mutagenic events in the more rapidly expanding progenitor pool (Bonnet and Dick 1997;Cozzio et al, 2003;Rossi et al, 2008). Similarly, adult SVZ NSCs have been proposed as the origin of gliomas and astrocytomas (Lewis 1968;Vick et al, 1977;Holland et al, 2000;Sanai et al, 2005;Zhu et al, 2005;Jackson et al, 2006).…”