Periodic Reporting for period 2 - Hemstem (Targeting leukaemia by modulating hematopoietic stem cell competitiveness)
Période du rapport: 2022-07-01 au 2023-12-31
The outlook for patients with acute myeloid leukemia has improved over the past years but still more than half of younger adults and about 90% of elderly patients diagnosed with AML die from the disease. Disease relapse is a main cause of death, and hematopoietic stem cell transplantation the best treatment option for inducing cure.
While the genetic landscape of acute myeloid leukemia cells has been widely studied, the mechanisms driving disease relapse remain ill-defined. Relapse is thought to occur from subpopulations of leukemic cells with stem cell properties. These so-called leukemic stem cells reside in the bone marrow and require close interactions with the microenvironment and other extracellular components for their maintenance and expansion. In this project, we further investigate the of leukemic stem cells with the bone marrow and with healthy hematopoietic cells that naturally locate there. The overall aim of is to identify, based on this knowledge, novel therapeutic strategies that can improve stem cell transplantation therapies and pave the way for their clinical translation to patients.
While the genetic landscape of acute myeloid leukemia cells has been widely studied, the mechanisms driving disease relapse remain ill-defined. Relapse is thought to occur from subpopulations of leukemic cells with stem cell properties. These so-called leukemic stem cells reside in the bone marrow and require close interactions with the microenvironment and other extracellular components for their maintenance and expansion. In this project, we further investigate the of leukemic stem cells with the bone marrow and with healthy hematopoietic cells that naturally locate there. The overall aim of is to identify, based on this knowledge, novel therapeutic strategies that can improve stem cell transplantation therapies and pave the way for their clinical translation to patients.
We have identified WNT signaling as a major pathway regulating the interactions of leukemic and healthy hematopoietic cells and provide molecular and functional proof-of-principle data in animal models demonstrating WNT pathway modulation during leukemogenesis. Additionally, we identified laminin-binding integrins as important mediators of leukemic cell interactions with the bone marrow environment. Importantly, different integrins are expressed on leukemic stem cells as opposed to healthy cells, providing a possibility for selective leukemia targeting. Finally, leukemic cell interactions with the environment were found to include the processing of matrix components such as collagen. To prepare the next step of clinical translation, we have refined our academic GMP-grade cell therapy manufacturing and successfully transferred an in-house produced cell therapy product to patients.
Our results identify new effects of WNT signaling modulation for AML therapy. Moreover, novel innovative strategies of targeting leukemic stem cells by disrupting their interaction with the environment are about to emerge from our studies and will be reported by the end of the project. We expect to generate, amongst other, convincing proof-of-principle data for an improved cell therapy product that can be then transferred as a next step to a clinical trial in patients, using the academic GMP-grade cell therapy manufacturing laboratory established under my lead in our department. Altogether, this project may induce a paradigm-shift in the clinical management of leukemia and clinical stem cell transplantation protocols.