Program Leader: Daniel G. Tenen, MD

Click here to download the HSCI Blood Diseases Program Overview.

Despite excellent characterization and clinical use, only one third to half of patients currently benefit from bone marrow and cord blood transplants. This is due to incomplete understanding of the process of stem cell self-renewal and to the inadequate sources of blood stem cells. A key to unlocking the therapeutic potential of stem cells is to identify the molecules involved in this process and decipher how they coordinately carry out the self-renewal program. The HSCI Blood Program seeks to define the innate mechanism of self-renewal of blood stem cells with the goal is of identifying molecular targets that turn on or off the self-renewal program. Turning on self-renewal is critical for expanding stem cells as needed for regenerating damaged tissues; turning off self-renewal is critical for interrupting the cancer stem cell perpetuation of malignancy.

Initiated three years ago, the HSCI Blood Program counts among its accomplishments to date:

1)    conducting screens for self-renewal in hematopoietic stem cells (HSCs) from human cells and in mouse and zebrafish models
2)    identifying and verifying several new candidate mediators of HSC self-renewal. One common mediator identified by several groups is a signaling pathway utilized in development, the Wnt/beta-catenin pathway
3)    initiating a clinical trial of a drug to augment HSC self-renewal, again using agents affecting the Wnt/beta-catenin pathway
4)    developing a bioinformatics/computational platform, including assembly of datasets on a new HSCI website, additional dataset collection and data analysis.

This program coordinates the efforts of five principal laboratories:

The Scadden lab focuses on two aspects of blood stem cell biology immediately relevant to patients: first, the process of stem cell expansion critical for improving the safety and effectiveness of stem cell transplantation; second, the process of differentiation that is blocked in acute myeloid leukemia and that, if restored, can result in effective treatment. The approach in each case is to move biological study to drug discovery.

The Zon lab found a small molecule (dimethyl prostaglandin E2) that could amplify blood stem cells and therefore help patients who are receiving bone marrow transplants or cord blood transplants where stem cells are frequently limited and insufficient for treatment to be successful. A combination of chromatin factors (the DNA, plus associated proteins) could participate in the self-renewal process. The plan is to perform a genetic screen for epigenetic factors required to produce hematopoietic stem cells (HSCs) in the aorta region and examine the mechanism of action of these factors.

A hallmark of stem cells is the capacity to self-renew and give rise to more identical stem cells. This property is shared in cancer, but in this context self-renewal is not regulated in the normal fashion. The Orkin lab plans to characterize the basis of self-renewal in HSCs through the study of nuclear proteins and protein complexes (histones) that control chromatin. The work focuses on interrogating the roles of specific histones in both normal hematopoiesis (development of blood cells) and in leukemia. The hypothesis is that specific histone modifying enzymes are required for proper HSC self-renewal and that perturbation of their expression contributes to self-renewal in leukemia.

The Armstrong laboratory focuses on the leukemic stem cell, how it is controlled, and how to develop means of targeting it selectively while sparing normal stem cells. To date, a major obstacle to curing leukemia is the limited understanding of self-renewal pathways in this disease. This lab’s use of a model in which the human MLL-AF9 leukemia gene is used to induce leukemia in mouse models has led to the discovery of a critical role for beta-catenin in leukemia self-renewal. Since leukemia stem cells cannot develop and thrive without this pathway it suggests that selectively targeting this pathway could prevent the growth of leukemic, but not normal stem cells, presenting a new therapeutic opportunity.

Over the years, the Tenen lab has studied key regulators of hematopoietic stem cell (HSC) differentiation, most notably a class of genes called transcription factors. Transcription factors control the expression of other genes. Recent results from his laboratory have demonstrated that one transcription factor, called C/EBPalpha, controls the ability of HSCs to divide, reproduce, and differentiate into more functional blood cells, the white cells which fight infection. If C/EBPalpha is down-regulated, as often happens in leukemia, then normal HSCs do not differentiate, but instead divide and reproduce. By performing genetic screens, the laboratory has isolated a number of downstream effectors of this pathway. The focus of current research is to investigate genes which affect C/EBPalpha function in normal and leukemic models and exploit them as drug targets.

More broadly, in addition to tackling specific diseases of the blood, the Blood Program expects that through focusing on one of the best understood organs – the blood system – its work will help researchers in other disease areas by determining if and how stem cells in different tissues share regulatory mechanisms. 

Pilot Grants