The MLLgnant Consequences of Reverting to an Embryonic Transcriptional Program

Stem Cell Research Program, Division of Hematology/Oncology, Moores UCSD Cancer Center, University of California-San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
Cell stem cell (Impact Factor: 22.27). 03/2009; 4(2):97-8. DOI: 10.1016/j.stem.2009.01.008
Source: PubMed


In this issue of Cell Stem Cell, Somervaille et al. (2009) have demonstrated convincingly that reversion to an embryonic transcriptional program through defective MLL gene expression contributes to the generation of myeloid leukemia stem cells.

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    • "Diagnostic and therapeutic strategies that predict and prevent cancer progression represent compelling unmet medical needs. While advanced cancers are diverse in phenotype, they often share essential functional properties ascribed to stem cells such as the capacity to become quiescent, acquire multi-lineage differentiation potential, survive and self-renew [1]. Early insight into the molecular pathogenesis of cancer stemmed from the discovery of activating oncogenes such as the Philadelphia chromosome positive (Ph+), and its constitutively active BCR-ABL protein tyrosine kinase product, in chronic myeloid leukemia (CML) [2–4]. "
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    ABSTRACT: Leukemia progression and relapse is fueled by leukemia stem cells (LSC) that are resistant to current treatments. In the progression of chronic myeloid leukemia (CML), blast crisis progenitors are capable of adopting more primitive but deregulated stem cell features with acquired resistance to targeted therapies. This in turn promotes LSC behavior characterized by aberrant self-renewal, differentiation, and survival capacity. Multiple reports suggest that cell cycle alterations, activation of critical signaling pathways, aberrant microenvironmental cues from the hematopoietic niche, and aberrant epigenetic events and deregulation of RNA processing may facilitate the enhanced survival and malignant transformation of CML progenitors. Here we review the molecular evolution of CML LSC that promotes CML progression and relapse. Recent advances in these areas have identified novel targets that represent important avenues for future therapeutic approaches aimed at selectively eradicating the LSC population while sparing normal hematopoietic progenitors in patients suffering from chronic myeloid malignancies.
    Current Hematologic Malignancy Reports 03/2012; 7(2):125-32. DOI:10.1007/s11899-012-0121-6 · 2.20 Impact Factor
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    ABSTRACT: RESUMEN Desde hace años sabemos que los tumores son masas celulares con un crecimiento anómalo, que causan la invasión y destrucción de órga-nos y tejidos y, si no se detienen a tiempo, causan la muerte del indi-viduo. Sin embargo, la masa tumoral dentro de un tumor sólido o las células del cáncer que componen una leucemia son heterogéneos en cuanto a las células que lo componen. Hoy sabemos que, entre los tipos celulares que podemos encontrar dentro de un tumor, existe un pequeño grupo de células que son responsables de poder trasplantar este tumor en un ratón inmunodeprimido (ratón desnudo, nude mice) y formar un nuevo tumor con las mismas características que el tumor original. La gran mayoría de las células tumorales, carecen de esta propiedad y tras su trasplante, las células se pierden y el tumor nunca aparece. Estas células que son capaces de reproducir el mismo tumor en otro animal, y probablemente las mismas que son capaces de crear metástasis en otras zonas del cuerpo, son denominadas Células Madre del Cáncer (CSC). Si estas células son las responsables de inducir o de mantener el cáncer su estudio nos permitirá, no solamente conocer mejor las bases celulares y moleculares del cáncer, sino la posibilidad de abordar de una manera completa su tratamiento y curación. De estas células, de sus características y de los diferentes modelos y tipos de cáncer donde se han descubierto, trata esta revisión. Para que un cáncer se cure, es ne-cesario y suficiente eliminar las CSC. AUGUSTO SILVA GONZÁLEZ 170 ABSTRACT We have known for many years that tumors are cellular masses with an abnormal growth that cause invasion and destruction of organs and tissues, and that, if they are not stopped, lead to death of the individual. Inside the tumor mass o among leukaemia tumoral cells, however, there is heterogeneity regarding cell types. We now know that among the cell types that we can find within a tumor, it exists a small group of cells which are responsible for a new tumor growth if they are transplanted to nude mice; this tumor would have the same characteristics as the original. The majority of tumoral cells lack this property and, after a transplant, they are lost and do not produce a new tumor.
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    ABSTRACT: The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, whole-transcriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU.1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.
    Proceedings of the National Academy of Sciences 12/2012; 73(8 Supplement). DOI:10.1073/pnas.1213021110 · 9.67 Impact Factor
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