Back to search

BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Neuroglial Regulation of the Haematopoietic Stem Cell Niche in Acute Myeloid Leukaemia Transformation

Alternative title: Nevro-gliacellers påvirkning av den hematopoetiske stamcellenisjen under utvikling av akutt myeloid leukemi

Awarded: NOK 7.0 mill.

Acute myeloid leukemia (AML) is a highly aggressive type of cancer, where abnormal white blood cells grow fast and accumulate inside the bone cavity. AML is the most common acute form of leukemia in adults, its incidence increases with age and the prognosis remains bleak. Overcoming these problems will require better understanding of AML. Some genetic lesions frequent in human AML are only able to induce mild chronic blood disorders in mouse models. This indicates that other factors must influence the process, like additional genetic mutations. The novel hypothesis that we are testing here is that miscommunication within niche cells that control the normal function of blood stem cells may influence AML. In spite of significant delays due to external reasons that the group has experienced throughout the years, we have been able to make significant contributions to the objectives of the project. Neuropathy of the bone marrow is present and essential for disease development in experimental models of JAK2-V617F+ myeloproliferative neoplasms (MPN) and MLL-AF9+ acute myeloid leukemia (AML), and it is present in the bone marrow of human MPN patients. Here, we show that neuropathy emerges in two additional experimental models of hematological disease including pre-leukemic myelopoiesis driven by NRAS-G12D and lymphoma/lymphoblastic leukemia driven by p53 deletion, as well as in AML patients, and it involves severe ultrastructural damage as shown by electron microscopy. When further reinforced chemically, neuropathy promotes malignancy substantially in the experimental NRAS-G12D mouse model. Together, bone marrow neuropathy is a common event in hematopoietic malignancies that involves profound degradation of sympathetic fibres and contributes to disease. This should be taken in consideration in the clinic, given that chemotherapy induces neuropathy of the bone marrow and is the most frequent first line treatment for AML and acute lymphoblastic leukemia patients. Further, we have found that low anti-inflammatory IL-1 receptor antagonist (IL-1RN) is frequent in AML patients and represents a prognostic marker of reduced survival. Treatments with IL-1RN and the IL-1ß monoclonal antibody canakinumab reduce the expansion of leukemic cells, including leukemic progenitors, in AML xenografts. In vivo deletion of IL-1rn induces HSC differentiation into the myeloid lineage and hampers B cell development via transcriptional activation of myeloid differentiation pathways at least partially dependent on the transcription factor NF?B. Low IL-1rn is present in an experimental model of pre-leukemic myelopoiesis driven by NRAS-G12D, and IL-1rn deletion promotes myeloproliferation, which relies on the bone marrow hematopoietic and stromal compartments. Conversely, IL-1rn protects against pre-leukemic myelopoiesis. Our data reveal that HSC differentiation is controlled by balanced IL-1ß/IL-1rn levels under steady-state, and that loss of repression of IL-1ß signaling may underlie pre-leukemic lesion and AML progression (Nature Communications, 2023). This project provides insights into the basic processes that regulate blood stem cell function/dysfunction and knowledge of markers for patient prognosis, and we will apply this knowledge to improve therapies against AML in the future.

Our work in this project can be divided in two main subprojects. Regarding the bone marrow neuropathy, we provided extensive evidence that it may be an ubiquitous event not restricted to myeloid malignancies that involves severe damage of sympathetic fibres at the ultrastructural level and contributes to disease. Given that chemotherapy induces neuropathy of the hematopoietic stem cell niche and is the most frequent first line treatment for patients with acute leukemias and chronic neoplasms, its use should be evaluated with caution on an individual basis in the clinic. We further open new avenues for future work with clinical implications. Briefly, neuropathy in hematopoietic malignancies may contribute to further complications as it has previously been linked to retinopathy in diabetes. Conversely, our data provide grounds for bone marrow dysfunction in unrelated non-hematopoietic diseases that course with bone marrow neuropathy such as diabetic neuropathy. This part of the work in under submission. In a second part of the work, we showed that low IL-1ß endogenous regulatory cytokine, IL-1 receptor antagonist (IL-1RN), from either the hematopoietic or the stromal compartment, contributes to biased myelopoiesis in the presence of pre-leukaemic lesions in mouse models, is a prognostic marker for reduced survival in acute myeloid leukemia patients, and provides a new rationale for IL-1ß blockade therapeutic potential (Nat Commun, 2023). In the follow up of this work, funded by NFR under the project 326530, we will now determine the genetic/epigenetic mechanisms associated to low IL1RN within acute myeloid leukemia CD34+ progenitors and their mesenchymal stromal cell niche. The next step will be the planning of a future Clinical Trial. The outcome our research has pinpointed drugs that may be beneficial for acute myeloid leukemia patients, and it is now our aim to select the patients with best chances to benefit from them. These drugs are FDA-approved, and used safely in unrelated diseases. This means that in the future, we will be able to apply for a Phase II/III Clinical Trial.

Acute myeloid leukaemia (AML) is the most common form of acute leukaemia occurring in adults, its incidence increases with age and the prognosis for the older patient remains bleak. Overcoming these problems will require improved understanding of AML. It has been proposed that the presence of mutations in at least two genes that specifically confer a survival advantage to the haematopoietic stem cell (HSC) and impede its further differentiation is required for AML development. This suggestion is based on the fact that oncogenes that confer a survival advantage to the HSC and are frequently mutated in human AML, such as RAS and FLT3, are only able to induce myeloproliferative neoplasms (MPN) in mouse models. Indeed, this indicates that these lesions are insufficient to cause AML and suggests that other factors must participate in the process. Until recently the focus has been on the search for additional genetic mutations with little consideration of the bone marrow HSC niche. The latter has a significant influence on haemopoiesis both under healthy conditions as well as in JAK2-V617F+ MPN pathological conditions. The potential role of the BM niche in the transition from MPN to AML and the importance of this to human AML will be investigated as the primary aim of this project. Thus, the results of this project have a strong translational potential. The present research will provide not only with insights into the basic processes that regulate HSC function/dysfunction, but also with knowledge of early markers for patient diagnosis/prognosis and will apply this knowledge in search of novel therapies against AML.

Publications from Cristin

No publications found

Funding scheme:

BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering