New Technique Helps Identify Leukemia Initiating Cells

Acute promyelocytic leukemia (APL) is associated with the accumulation of promyelocyte cells in the bone marrow and blood. A majority of APL patients have a chromosomal translocation leading to the expression of a certain protein (promyelocytic-retinoic acid receptor alpha protein). In most patients, treatment with retinoic acid eliminates this protein and causes the leukemia cells to disappear. However, in some patients that does not work.  The cause of this failure has been hypothesized to be due to the continued existence of cancer “stem” cells. In order to identify the cell population that may be responsible for resistance to retinoic acid treatment, HSCI Principal Faculty Member and Head of the HSCI Blood Diseases Program Dan Tenen and fellow researchers used a new approach to sorting myeloid cells from mice at different stages of differentiation. In a recent paper, they showed they can isolate a particular group of myeloid cells that accumulate in the spleen and bone marrow of a mouse model of APL. Further, they showed that these cells are capable of generating leukemia in mice, suggesting that they are APL cancer-initiating cells. These results shed light on the mechanisms involved in the etiology of APL and also contribute to our understanding of how a committed progenitor cell population can cause the disease.

Guibal FC, Alberich-Jorda M, Hirai H, Ebralidze A, Levantini E, Di Ruscio A, Zhang P, Santana-Lemos BA, Neuberg D, Wagers AJ, Rego EM, Tenen DG. Blood. (2009). Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia. Blood 114, 5415-25.

New Gene Cassette Approach Plays a Promising Tune for Induced Pluripotency

Somatic cells can be reprogrammed to a pluripotent state by the introduction of a defined group of transcription factors. Previous methods have relied on viral vectors for the introduction of these factors, an approach that has a number of drawbacks including low efficiency and the introduction of potentially harmful factors into cells. Other protocols, using drug-inducible vectors have the drawbacks of showing variable expression and effects on the expression of endogenous genes. In an effort to improve upon existing approaches, HSCI Principal Faculty member Konrad Hochedlinger and colleagues recently published a new approach that avoids these undesirable shortcomings. The researchers used a gene targeting approach to integrate a “cassette” containing the four transcription factors needed for reprogramming into embryonic stem cells.  Introducing the reprogramming factors by these means was sufficient to keep the embryonic stem cells pluripotent without the need for any other factors and did so at an efficiency rate that was tenfold higher than the previously used drug-inducible system. These results provide an exciting opportunity to create induced pluripotent cell lines at a much higher efficiency rate without many of the drawbacks of other methods. This advance will also enable future studies which will inform our understanding of how somatic cells can be converted into induced pluripotent cells and whether embryonic stem cells and induced pluripotent cells are indeed functionally equivalent.

Stadtfeld, M., Maherali, N., Borkent, M., Hochedlinger, K. (2010). A reprogrammable mouse strain from gene-targeted embryonic stem cells.
Nat Methods 1, 53-5.

Cell Fate Decisions Best Made with a Partner

The balance between cell self-renewal and differentiation is orchestrated by a number of factors and mechanisms that are not yet completely understood. A recent paper published by HSCI Principal Faculty member Stuart Orkin and colleagues sheds light on this complex process. Orkin and colleagues discovered a role for a factor named Jumonji (JMJ) that associates with a particular set of factors (Polycomb repressive complex 2 (PRC2)), which in turn had been previously found to help regulate the balance between self-renewal and differentiation by affecting methylation on a particular protein in the cell nucleus. The new experiments showed that JMJ acts with PRC2 by modulating its activity and that this interaction fine-tunes the balance between self-renewal and differentiation. Such an understanding is particularly valuable because this knowledge could help inform therapeutic approaches by giving scientists the toolbox to shift the cell fate balance, for example enabling the creation of a reservoir of undifferentiated stem cells that might be a resource for cell replacement or tissue engineering applications.

Shen, X., Kim, W., Fujiwara, Y., Simon, M.D., Liu, Y., Mysliwiec, M.R., Yuan, G.C., Lee, Y., Orkin, S.H. (2009). Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell 139, 1303-14.