Abstract
Acute promyelocytic leukemia (APL) is characterized by hyperproliferation of promyelocytes, progenitors that are committed to terminal differentiation into granulocytes, making it an ideal disease in which to study the transforming potential of less primitive cell types. We utilized a murine model of APL in which the PML–RARα oncogene is expressed from the endogenous cathepsin G promoter to test the hypothesis that leukemia stem cell (LSC) activity resides within the differentiated promyelocyte compartment. We prospectively purified promyelocytes from transgenic mice at various stages of disease and observed that PML–RARα-expressing promyelocytes from young preleukemic mice had acquired properties of self-renewal both in vitro and in vivo. Progression to acute leukemia was associated with an expansion of the promyelocyte compartment at the expense of other stem, progenitor and terminally differentiated populations. Leukemic promyelocytes exhibited properties of self-renewal, and were capable of engendering leukemia in secondary recipient mice. These data indicate that PML–RARα alone can confer properties of self-renewal to committed hematopoietic progenitors before the onset of disease. These findings are consistent with the hypothesis that cancer stem cells may arise from committed progenitors that lack stem cell properties, provided that the initiating mutation in cancer progression activates programs that confer properties of self-renewal.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hope KJ, Jin L, Dick JE . Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 2004; 5: 738–743.
Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994; 367: 645–648.
So CW, Karsunky H, Passegue E, Cozzio A, Weissman IL, Cleary ML . MLL-GAS7 transforms multipotent hematopoietic progenitors and induces mixed lineage leukemias in mice. Cancer Cell 2003; 3: 161–171.
Lavau C, Szilvassy SJ, Slany R, Cleary ML . Immortalization and leukemic transformation of a myelomonocytic precursor by retrovirally transduced HRX-ENL. EMBO J 1997; 16: 4226–4237.
Passegue E, Wagner EF, Weissman IL . JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 2004; 119: 431–443.
Neering SJ, Bushnell T, Sozer S, Ashton J, Rossi RM, Wang PY et al. Leukemia stem cells in a genetically defined murine model of blast-crisis CML. Blood 2007; 110: 2578–2585.
Cozzio A, Passegue E, Ayton PM, Karsunky H, Cleary ML, Weissman IL . Similar MLL-associated leukemias arising from self-renewing stem cells and short-lived myeloid progenitors. Genes Dev 2003; 17: 3029–3035.
Passegue E, Jamieson CHM, Ailles LE, Weissman IL . Normal and luekemic hematopoiesis: are leukemias a stem cell disorder or a reaquisition of stem cell characteristics? PNAS 2003; 100: 11842–11849.
Reya T, Morrison SJ, Clarke MF, Weissman IL . Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–111.
Huntly BJ, Shigematsu H, Deguchi K, Lee BH, Mizuno S, Duclos N et al. MOZ-TIF2, but not BCR-ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 2004; 6: 587–596.
Krivtsov AV, Twomey D, Feng Z, Stubbs MC, Wang Y, Faber J et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 2006; 442: 818–822.
Westervelt P, Lane AA, Pollock JL, Oldfather K, Holt MS, Zimonjic DB et al. High-penetrance mouse model of acute promyelocytic leukemia with very low levels of PML-RARalpha expression. Blood 2003; 102: 1857–1865.
Lee BH, Tothova Z, Levine RL, Anderson K, Buza-Vidas N, Cullen DE et al. FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell 2007; 12: 367–380.
Akashi K, Traver D, Miyamoto T, Weissman IL . A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 2000; 404: 193–197.
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 2003; 4: 249–264.
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 2004; 5: R80.
Higuchi M, O'Brien D, Kumaravelu P, Lenny N, Yeoh EJ, Downing JR . Expression of a conditional AML1-ETO oncogene bypasses embryonic lethality and establishes a murine model of human t(8;21) acute myeloid leukemia. Cancer Cell 2002; 1: 63–74.
Deguchi K, Ayton PM, Carapeti M, Kutok JL, Snyder CS, Williams IR et al. MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP. Cancer Cell 2003; 3: 259–271.
Anderson KL, Smith KA, Pio F, Torbett BE, Maki RA . Neutrophils deficient in PU.1 do not terminally differentiate or become functionally competent. Blood 1998; 92: 1576–1585.
Zimonjic DB, Pollock JL, Westervelt P, Popescu NC, Ley TJ . Acquired, nonrandom chromosomal abnormalities associated with the development of acute promyelocytic leukemia in transgenic mice. Proc Natl Acad Sci USA 2000; 97: 13306–13311.
Kelly PN, Dakic A, Adams JM, Nutt SL, Strasser A . Tumor growth need not be driven by rare cancer stem cells. Science 2007; 317: 337.
Minucci S, Monestiroli S, Giavara S, Ronzoni S, Marchesi F, Insinga A et al. PML-RAR induces promyelocytic leukemias with high efficiency following retroviral gene transfer into purified murine hematopoietic progenitors. Blood 2002; 100: 2989–2995.
Zheng X, Beissert T, Kukoc-Zivojnov N, Puccetti E, Altschmied J, Strolz C et al. Gamma-catenin contributes to leukemogenesis induced by AML-associated translocation products by increasing the self-renewal of very primitive progenitor cells. Blood 2004; 103: 3535–3543.
Turhan AG, Lemoine FM, Debert C, Bonnet ML, Baillou C, Picard F et al. Highly purified primitive hematopoietic stem cells are PML-RARA negative and generate nonclonal progenitors in acute promyelocytic leukemia. Blood 1995; 85: 2154–2161.
Edwards RH, Wasik MA, Finan J, Rodriguez R, Moore J, Kamoun M et al. Evidence for early hematopoietic progenitor cell involvement in acute promyelocytic leukemia. Am J Clin Pathol 1999; 112: 819–827.
Lane AA, Ley TJ . Neutrophil elastase cleaves PML-RARalpha and is important for the development of acute promyelocytic leukemia in mice. Cell 2003; 115: 305–318.
Lane AA, Ley TJ . Neutrophil elastase is important for PML-retinoic acid receptor alpha activities in early myeloid cells. Mol Cell Biol 2005; 25: 23–33.
Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE . Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 2006; 12: 1167–1174.
Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441: 475–482.
Krause DS, Lazarides K, von Andrian UH, Van Etten RA . Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells. Nat Med 2006; 12: 1175–1180.
Acknowledgements
We thank Maricel Gozo and Dena Leeman for technical support, as well as Stefan Fröhling, Claudia Scholl and all the members of the Gilliland laboratory for helpful discussions and comments regarding this study. DGG is a Doris Duke Foundation Distinguished Clinical Scientist and a Howard Hughes Medical Institute investigator. Supported in part by National Institute of Health grants DK50654 and CA66996 and by the Leukemia and Lymphoma society to DGG.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)
Rights and permissions
About this article
Cite this article
Wojiski, S., Guibal, F., Kindler, T. et al. PML–RARα initiates leukemia by conferring properties of self-renewal to committed promyelocytic progenitors. Leukemia 23, 1462–1471 (2009). https://doi.org/10.1038/leu.2009.63
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2009.63
Keywords
This article is cited by
-
The PML-RARA fusion is not detectable in historical blood samples of acute promyelocytic leukaemia patients
Annals of Hematology (2022)
-
A novel fusion protein TBLR1-RARα acts as an oncogene to induce murine promyelocytic leukemia: identification and treatment strategies
Cell Death & Disease (2021)
-
All-trans retinoic acid and arsenic trioxide fail to derepress the monocytic differentiation driver Irf8 in acute promyelocytic leukemia cells
Cell Death & Disease (2017)
-
Pituitary adenylate cyclase-activating polypeptide (PACAP) contributes to the proliferation of hematopoietic progenitor cells in murine bone marrow via PACAP-specific receptor
Scientific Reports (2016)
-
Origins of aberrant DNA methylation in acute myeloid leukemia
Leukemia (2014)