Jerald Radich, MD

2010-03-01

Dr. Radich indicated no relevant conflicts of interest.

Guibal FC, Alberich-Jorda M, Hirai H, et al. Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia. Blood. 2009;114:5415-25.

Acute promyelocytic leukemia (APL) is a distinct form of acute myeloid leukemia (AML) distinguished by the accumulation of promyelocytic blasts. Genetically, APL is defined by translocations involving the retinoic acid receptor alpha (RARA) from chromosome 17; the vast majority of these translocations partner with the PML gene from chromosome 15. The chimeric PML/RARA protein complexes with protein co-repressors having histone deacetylase and methylase activity. Therapy with a combination of all trans retinoic acid (ATRA) and arsenic is fantastically effective, with survival rates of approximately 90 percent (reviewed¹). ATRA releases the block of differentiation mainly by binding with PML-RARA, allowing for transcriptional activation. Arsenic appears to work primarily by facilitating PML-RARA protein degradation. In murine models, both agents appear necessary to redress the differentiation and self-renewal disturbances in the APL stem cell,² similar to the human experience of the added benefit of adding arsenic to ATRA. The combination of a molecular lesion (PML/RARA) and a phenotypic target (promyelocytes) make APL a model disease for tracking down and isolating the near-mystical “leukemia stem cell” (also known as the leukemia-initiating cell, or LIC).

In a series of elegant and logical experiments, Guibal et al. from Dan Tenen’s group at Harvard appear to have identified and isolated the APL-initiating cell (at least, in a genetically manipulated murine model). The authors first characterized normal mouse hematopoetic differentiation via a complex set of surface antigens and flow cytometry that they compared to leukemia cells generated in their murine APL model. A PML/ RARA transgenic mouse was used to create APL cells that were then transplanted into isogenic mice (since the PML/RARA mice die of other complications that make it difficult to study the leukemia). The secondary transplanted mice developed leukemia with a huge promyelocytic excess. Promyelocytic cells (defined in mice as CD34+/c-kit+/FcγRIII/II+/ Gr1i^nt) were isolated from the bone marrow of these mice by fluorescence-activated cell sorting and were found to be the population that could initiate APL when transplanted into yet another mouse. The onset of the leukemia nicely depended on the dose of LICs. The mice transplanted with LICs developed a similar phenotype as the mice transplanted with undifferentiated cells, suggesting that the LIC alone was sufficient to create APL. Lastly, the authors found that the transcription factor C/EBPA, known to be essential in normal myeloid differentiation, was down-regulated in LIC. Moreover, when PML/RARA mice were cross-bred with C/EBPA +/- mice, the resulting leukemia had a shorter latency than in mice with normal amounts of C/EBPA protein, suggesting a direct link between PML/ RARA, C/EBPA expression, and APL.

Why is this study important? First and perhaps foremost, the study has created a model for the study of the stem cell biology in APL; more generally, this paper offers a plan for the creation of other murine models for different genetic subsets of leukemia. The potential limitation of the study in reference to human APL is that, in the PML/RARA transgenic murine model, all cells, including the most immature of the hematopoietic cells, have the PML/RARA gene. In human APL, it is not clear whether the CD34 compartment is involved.³ Nonetheless, the ability to create, characterize, and isolate models of human leukemia should broaden our understanding of how leukemia works and how to kill it.

1. Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Blood. 2009;114:5126-35.
2. Nasr R, Guillemin MC, Ferhi O, et al. Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation. Nat Med. 2008;14:1333-42.
3. Turhan AG, Lemoine FM, Debert C, et al. Highly purified primitive hematopoietic stem cells are PML-RARA negative and generate nonclonal progenitors in acute promyelocytic leukemia. Blood. 1995;85:2154-61.

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