Leukemia, leukemic stem cells and the the hematopoietic stem cell niche

Group Members: Matilda Rehn, Kristian Reckzeh and Jörg Cammenga

Role of transcription factors in the pathogenesis of AML

The genetic alterations in acute myelogenous leukemia (AML) often affect transcription factors that also have an important role in normal hematopoiesis. The transcription factors disrupted in AML can be classified into three different groups: 1) lineage-specific transcription factors, which play pivotal roles in the differentiation process of a specific lineages [e.g. the CAAT/enhancer binding factor alpha (C/EBPa), a key regulator of granulopoiesis; the ETS transcription factor PU.1, which is instrumental in determining cell fate into the myeloid lineage; the zinc-finger transcription factor GATA-1, an important regulator of erythro- and megakaryopoiesis; and the retinoic acid receptor alpha (RARA); 2) transcription factors that are expressed in multiple lineages, and which are probably more aptly designated transcriptional organizers (e.g. the core binding factor (CBF) family, and the C2H2 zinc-finger transcription factor EVI-1); and 3) transcription factors that are generally thought to orchestrate global changes in transcriptional control during tissue development (e.g. homeobox proteins, such as the HOX genes). Our lab is mainly interested in the role of AML1, GATA-1 and C/EBPa in the pathogenesis of AML. As an experimental system we use retroviral gene transfer of the mutant transcription factor into murine and human hematopoietic stem cells to test how they affect normal hematopoietic differentiation.

Identification of the leukemic stem cell and the implication on therapy

Hematopoiesis is a hierarchical process starting with the long-term repopulating stem cell (HSC) that further differentiates via the multi-potential progenitor (MPP) cell into the common myeloid progenitor (CMP) and the common lymphoid progenitor (CLP). The lineage restricted CMP cell gives rise to the granulocyte/macrophage progenitor (GMP) which then terminally differentiates into mature granulocytes and macrophages / monocytes. It has been proposed that acute myelogenous leukemia (AML) arises from a leukemic stem cells but whether this leukemic stem cell is a hematopoietic stem or a progenitor cell that has acquired a genetic alteration remains elusive. This question is not only of interest for the better understanding of leukemogenesis but does also have a big impact on the therapy of this disease.

Characterization of the hematopoietic stem cell niche

Hematopoiesis is a hierarchical process that originates with the long-term repopulating hematopoietic stem cell (HSC). Due to a process called asymetrical division, the HSC creates a new stem cell and a short-term repopulating cell which further differentiates into the multi-lineage progenitor (MPP) which then either forms the common myeloid progenitor (CMP) or the common lymphoid progenitor (CLP).
Despite the tremendous advances in the field of stem cell biology, our knowledge about the molecular mechanisms underlying hematopoietic stem cell self-renewal remains very limited which hampers the growths of HSC in vitro. It has been proposed that stem cells reside in a specific niche which provides a special microenvironment (stem cell niche). The hematopoietic stem cell niche is located in the endosteal space where HSC are located in close proximity to osteoblasts and stroma cells which provide special growth factors to the HSC.
A better understanding of the physiologic conditions in which stem cells normally resides (stem cell niche) are needed to mimic these conditions to optimize in vitro culture conditions of hematopoietic stem cells. We are using different techniques, like gene expression analysis, retroviral expression of genes involved in self-renewal etc to investigate the effects of the HSC niche microenvironment on HSC self-renewal and maintenance.

Selected Recent and Key Publications

1. Jorg Cammenga, Stefan Horn, Ulla Bergholz, Gunhild Sommer, Peter Besmer, Walter Fiedler, and Carol Stockin. Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate. Blood. 2005 Dec 1;106(12):3958-61. Epub 2005 Aug 4.
2. Mulloy JC, Jankovic V, Wunderlich M, Delwel R, Cammenga J, Krejci O, Zhao.H, Valk PJ, Lowenberg B, Nimer SD. AML1-ETO fusion protein up-regulates TRKA mRNA expression in human CD34+ cells, allowing nerve growth factor-induced expansion. Proc Natl Acad Sci USA. 2005 Feb 24
3. Mulloy JC, Cammenga J, Berguido FJ, Wu K, Zhou P, Comenzo RL, Jhanwar S, Moore MAS, Nimer SD. Induction of human hematopoietic progenitor cell self-renewal and multi-lineage differentiation by AML1/ETO. Blood 2003 Dec 15; 102 (13):4369-76
4. Cammenga J, Mulloy JC, Berguido FJ, Viale A, Nimer SD. Induction of C/EBP alpha activity alters gene expression and differentiation of human CD34+ cells. Blood. 2003 Mar 15; 101 (6):2206-2214
5. Mulloy JC*, Cammenga J*, MacKenzie KL, Moore MAS, Nimer SD. The AML1/ETO fusion protein promotes the expansion of human hematopoietic stem cells. Blood. 2002 Jan 1; 99 (1):15-23.*equal contribution authors.
6. J Cammenga. Gatekeeper pathways and cellular background in the pathogenesis and therapy of AML. Leukemia. 2005 Oct;19(10):1719-28. Review.
7. Scandura JM, Boccuni P, Cammenga J, Nimer DS. Transcription factors fusions in acute leukemia: variations on a theme. Oncogene 2002 May 13; 21 (21): 3422-3444. Review.

Print version Tell a friend about this page