Common and Overlapping Oncogenic Pathways Contribute to the Evolution of Acute Myeloid Leukemias

Abstract

Fusion oncogenes in acute myeloid leukemia (AML) promote self-renewal from committed progenitors, thereby linking transformation and self-renewal pathways. Like most cancers, AML is a genetically and biologically heterogeneous disease, but it is unclear whether transformation results from common or overlapping genetic programs acting downstream of multiple mutations or by the engagement of unique genetic programs acting cooperatively downstream of individual mutations. This distinction is important, because the involvement of common programs would imply the existence of common molecular targets to treat AML, no matter which oncogenes are involved. Here we show that the ability to promote self-renewal is a generalized property of leukemia-associated oncogenes. Disparate oncogenes initiated overlapping transformation and self-renewal gene expression programs, the common elements of which were defined in established leukemic stem cells from an animal model as well as from a large cohort of patients with differing AML subtypes, where they strongly predicted pathobiological character. Notably, individual genes commonly activated in these programs could partially phenocopy the self-renewal function of leukemia-associated oncogenes in committed murine progenitors. Furthermore, they could generate AML following expression in murine bone marrow. In summary, our findings reveal the operation of common programs of self-renewal and transformation downstream of leukemia-associated oncogenes, suggesting that mechanistically common therapeutic approaches to AML are likely to be possible, regardless of the identity of the driver oncogene involved. Cancer Res; 71(12); 4117-29. Ó2011 AACR.

Recent advances in acute myeloid leukemia stem cell biology

“…19 In addition to MOZ-TIF2 and MLL-AF9, NUP98-HOXA9 and AML-ETO were also able to confer self-renewal properties to committed progenitors, although the latter was unable to transform these progenitors in vivo. 33 Interestingly, other oncogenes, including BCR-ABL, FLT3-ITD and co-expression of Hoxa9 and Meis1, were not able to alter the self-renewal properties of progenitors. 33,38,40 Instead, Hoxa9 and Meis1 or BCR-ABL were oncogenic only when expressed in HSC.…”

“…33 Interestingly, other oncogenes, including BCR-ABL, FLT3-ITD and co-expression of Hoxa9 and Meis1, were not able to alter the self-renewal properties of progenitors. 33,38,40 Instead, Hoxa9 and Meis1 or BCR-ABL were oncogenic only when expressed in HSC. 38,40 In accordance with this, in chronic myeloid leukemia (CML), the initiating chromosomal translocation t(9;22) leading to formation of the BCR-ABL fusion gene occurs in an HSC.…”

“…Despite heterogeneity with regard to the initiating mutation, common and overlapping downstream genes were identified including Bmi1, Meis1, Sox4, Tcf4, Hoxa9 and Smad7. 33 Interestingly, some of these genes were able to partially phenocopy the original mutation when over-expressed in murine bone marrow cells. Taken together, these findings suggest that common pathways which facilitate leukemic transformation exist downstream of a variety of different initiating mutations and identifies these pathways as potential therapeutic targets.…”

“…As an example, Myb was also demonstrated to be part of an immediate self-renewal program downstream of other oncogenes including NUP98-HOXA9 and MOZ-TIF2. 33 Therefore, there are likely to be common and overlapping pathways mediating self-renewal downstream of a variety of different initiating mutations that may also offer avenues of therapeutic intervention in a wider group of AML patients.…”

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

“…1 However, it is likely that AML share various survival pathways downstream of the driver mutations, making the existence of common survival pathways and therapeutic targets likely. 2 Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a member of the Cap 'n' Collar basic leucine zipper transcription factor family that protects cells from reactive oxygen species through the regulation of a number of cytoprotective genes including heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO1). [3][4][5] In cancer, NRF2 activation is pro-tumoural in a spectrum of malignancies through mutations in NRF2 or its cytosolic inhibitor KEAP1.…”