Hematopoiesis and Leukemogenesis

Hematopoiesis and Leukemogenesis2020-04-03T16:58:48+02:00

Project Description

Miriam Erlacher (MD, PhD)

Attending physician – Study Physician EWOG-MDS

E: miriam.erlacher@uniklinik-freiburg.de
T: +49 761 27043010
F: +49 761 27046230

Division of Pediatric Hematology and Oncology
Center for Pediatrics and Adolescent Medicine
Mathildenstraße 1
79106 Freiburg
Germany

Our research focuses on the role of apoptosis regulated by BCL-2 proteins the healthy and the diseased hematopoietic system, with special focus on human hematopoiesis, rare leukemias of childhood (e.g. juvenile myelomonocytic leukemia, MDS) and inherited bone marrow failure syndromes (e.g. dyskeratosis congenita, Fanconi anemia). We also aim at understanding syndromes predisposing to leukemia and the specific mechanisms of malignant transformation. Finally, it is our goal to generate model systems reminiscent of human disease and suitable for research with high translational potential.

RESEARCH THEMES

Apoptosis in the hematopoietic system and during leukemogenesis

As in other tissues, a tight regulation of survival and death decisions is required for maintenance, homeostasis and function of the hematopoietic system. Deregulation of apoptosis signaling contributes to many hematological diseases characterized by cytopenia (e.g. severe congenital neutropenia, bone marrow failure syndromes etc.). In addition, apoptosis signaling and its deregulation play major roles during leukemogenesis, and apoptosis resistance is regarded as one of the “hallmarks of cancer” required for full malignant transformation. There is, however, emerging evidence that apoptosis of premalignant cells does not always act as a barrier against malignant transformation but rather can drive compensatory proliferation and selection of individual clones. This drives, on a long run, genomic instability and facilitates the emergence of malignant clones (Figure 1).

Our research group is focusing on the role of BCL-2 protein regulated apoptosis in the healthy and the diseased hematopoietic system, with special focus on human hematopoiesis and rare leukemias of childhood (e.g. juvenile myelomonocytic leukemia, MDS secondary to bone marrow failure syndromes).

How apoptosis shapes cancer (Figure 1, taken from Labi & Erlacher, Cell Death & Disease, 2015)

Specifically, the aims of our research group are:

  1. to investigate how BCL-2 regulated apoptosis shapes the human hematopoietic system under physiological conditions;
  2. to characterize how apoptosis contributes to loss of hematopoietic stem and progenitor cells under conditions of stress (e.g. during chemotherapy or during transplantation) and to identify protective molecules that render human HSPCs more resistant;
  3. to describe how apoptosis and its deregulation contribute to hematological diseases with bone marrow failure; and
  4. to better define the different roles of apoptosis and apoptosis resistance, respectively, for tumor development, with special focus on rare childhood leukemias (e.g. JMML, transient myeloproliferation) and myeloid malignancies arising on the background of predisposition syndromes (e.g. inherited bone marrow failure syndromes).
  5. to generate good in vivo and in vitro disease model systems with high translational potential.

TEAM

SELECTED RECENT PUBLICATIONS

Azacitidine is effective for targeting leukemia-initiating cells in juvenile myelomonocytic leukemia. Krombholz, C. F., Gallego-Villar, L., Sahoo, S. S., Panda, P. K., Wlodarski, M. W., Aumann, K., Hartmann, M., Lipka, D. B., Daskalakis, M., Plass, C., Niemeyer, C. M., Erlacher, M.*, Flotho, C*. (2019). Leukemia (* shared last authors)

In vitro and in vivo evaluation of possible pro-survival activities of PGE2, EGF, TPO and FLT3L on human hematopoiesis. Demmerath, E. M., Bohler, S., Kunze, M., Erlacher, M. (2019). Haematologica 104, 669-677. Abstract

Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans. Buonocore, F., Kuhnen, P., Suntharalingham, J. P., Del, V., I, Digweed, M., Stachelscheid, H., Khajavi, N., Didi, M., Brady, A. F., Blankenstein, O., Procter, A. M., Dimitri, P., Wales, J. K. H., Ghirri, P., Knobl, D., Strahm, B., Erlacher, M., Wlodarski, M. W., Chen, W., Kokai, G. K., Anderson, G., Morrogh, D., Moulding, D. A., McKee, S. A., Niemeyer, C. M., Gruters, A., Achermann, J. C. (2017) J.Clin.Invest 127, 1700-1713. Abstract

Transient apoptosis inhibition in donor stem cells improves hematopoietic stem cell transplantation. Kollek, M., Voigt, G., Molnar, C., Murad, F., Bertele, D., Krombholz, C. F., Bohler, S., Labi, V., Schiller, S., Kunze, M., Geley, S., Niemeyer, C. M., Garcia-Saez, A., Erlacher, M. (2017) J.Exp.Med. 214, 2967-2983. Abstract

Long-term serial xenotransplantation of juvenile myelomonocytic leukemia recapitulates human disease in Rag2-/-gammac-/- mice. Krombholz CF, Aumann K, Kollek M, Bertele D, Fluhr S, Kunze M, Niemeyer CM, Flotho C*, Erlacher M*. Haematologica 2016; 101: 597-606. * shared last authorship. Abstract

FUNDING