Hong Qian

Drug resistance and relapse are the biggest challenges in treating leukemia. There is therefore a great need for more effective treatment methods to cure leukemia. To develop such treatments, it is important to understand how the leukemia-initiating stem cells (LSCs) can circumvent treatments. Studies have shown that the bone marrow microenvironment protects LSCs against treatment. So far, however, we know very little about which signaling pathways are altered in the bone marrow microenvironment and contribute to LSC survival and treatment resistance. This project aims to identify altered factors in the bone marrow microenvironment in patients with chronic myelogenous leukemia (CML) and evaluate their therapeutic effect on LSC survival and treatment response. The goal is to find factors that can be used to develop treatments to eliminate the treatment-resistant leukemia-initiating LSCs. We have characterized the bone marrow environment in newly diagnosed patients with CML and found several altered factors. In this project, we will study their prognostic role and therapeutic effect against leukemic cells from CML patients that are resistant to current chemotherapy. We hope to identify the critical molecules which may serve as new treatment targets specifically directed at CML LSC or prognostic markers regarding treatment response. These results will form the basis for studies of changes in the bone marrow microenvironment in another blood cancer, acute myeloid leukemia.

The main challenge for treating leukemias is therapy resistance, resulting in treatment failure and relapse, which ultimately leads to death. Consequently, there is an urgent need for more effective therapies. Accumulating evidence suggests that drug resistance and relapse is due to the persistence of residual leukemia-initiating stem cells (LSCs) that are protected by bone marrow (BM) microenvironment, the so-called niche. Thus, targeting the leukemia niche may offer new treatment options to sensitize to chemotherapy enabling LSC eradication to cure the diseases. However. little is known about the key niche factors contributing to LSC resistance and relapse. This projectaims to unravel critical molecular pathways mediating LSC interactions with their niche in acute and chronic myeloid leukemia and the functional impact of the pathways on therapy response of the LSC using both patient samples and mouse models. We have identified some the candidate niche factors including Lama4 and CXCL14. Here we will determine their therapeutic effects on the LSCs and the underlying mechanisms by RNA sequencing and metabolic assays in co-culture systems and patient-derived xenograft mouse models. CRISPR-based gene-editing or protein overexpression will be utilized to restore the candidate niche factor expression. The project will advance our knowledge about niche regulation of the leukemias and enable us to identify key molecules that can be targeted to overcome drug resistance.

We will combine our 20 year knowledge on the immunomodulatory properties of mesenchymal stromal cell (MSC) transplantation with results from 2 separate projects on neuroinflammation, i.e. multiple sclerosis (MS) and fatigue/cognitive dysfunction after hematopoietic stem cell transplantation (HSCT).We believe that stroma – immune – neuronal crosstalk is defective and that activated perivascular stroma in the CNS is deficient in trophic signals, secretes profibrotic matrix molecules and cytokines that propagate neuroinflammation. In MS, we will continue our characterization of fibrotic perivascular stroma of brain tissue and MSC from MS patients.After HSCT, we have identified patients with cognitive dysfunction, hypoactivation of the prefrontal cortex and decreased immune regulatory proteins and immune subsets in the CNS. We believe that deficiency of trophic signals from the perivascular stroma activate microglia and alloreactive T-cells in the CNS and disrupt synaptic function.In transgenic mice where transcription factor Ebf2 is GFP marked and Ebf2-CreER x Rosa26-DTA mice where MSC can be selectively eliminated by Tamoxifen, we will induce neuroinflammation and study the stroma in the early inflammatory events. Possible reversal of neuroinflammation will be studied after intranasal adoptive transfer of MSC.It is not until we understand the respective contributions of stroma, immune subsets and neurons that we can design targeted therapies in various neuroimmune disorders.

The biggest challenge for successful treatment of leukemias is therapy resistance, which leads to treatment failure, relapse and often death of the patient. There is an urgent need for better and more effective treatment methods. To develop such treatments, it is essential to understand how the leukemic stem cells (LSCs) can evade treatments and acquire a growth advantage. Recent studies have shown that leukemic cells can alter the bone marrow microenvironment so that LSCs are protected against chemotherapy. So far, it is largely unclear in detail how the bone marrow environment contributes to the survival of leukemic cells in this process. This project aims to identify leukemia-specific factors in the bone marrow microenvironment/niche that are important for LSC survival and are thereby linked to the development of myeloid leukemia and therapy resistance. We will characterize the bone marrow niche using advanced techniques such as flow cytometry and gene sequencing. Recently, we have shown that several factors of the bone marrow environment are altered in patients and in a mouse model with leukemia. In this project, we will use the CRISPR-based gene modification methods to evaluate the therapeutic potential and prognostic role of the altered niche factors for these leukemias. The results of these studies will increase our knowledge of how leukemic cells interact with their microenvironment and will help us identify the critical molecular signaling pathways, which may serve as new therapeutic targets to develop more effective treatments for myeloid leukemia. We hope to transfer the the potential results to the clinic to improve treatment outcomes in myeloid leukemias.

Current treatments for leukemia have dramatically improved the prognosis for patients with chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Although the development of cancer is alleviated, it is difficult to cure leukemia and eliminate the cancerous stem cells, resulting in lifelong treatments and high risk of relapse. Leukemic stem cells are found mainly in the bone marrow and are protected by the surrounding bone marrow environment, which includes bone, fat, cartilage and blood vessels. There is therefore a great need to identify new drugs targeting the bone marrow environment in order to improve treatment and maintain normal blood formation. This project aims to process the bone marrow environment around the cancer stem cells to reform function and restore it to normal blood formation. The bone marrow environment can indirectly contribute to the development of leukemia by protecting the cancer stem cells against treatment and helping them grow. In our research, we have seen that stromal cells in the bone marrow are altered in CML patients. With modern techniques such as FACS, RNA sequencing and DNA sequencing, as well as preclinical KML and AML mouse models, we want to study how the immediate environment is affected by cancer stem cells and find new strategies to eliminate cancer. Our goal is to identify the cellular and molecular interactions between the cells in the bone marrow environment and the leukemic stem cells, which can contribute to the pathogenesis of leukemia and have significance for the response to treatment. We hope to identify target substances for new targeted drugs that can contribute to better and more effective treatment methods for blood disorders such as KML or AML.

Current treatments for leukemia have dramatically improved the prognosis for patients with chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Although the development of cancer is alleviated, it is difficult to cure leukemia and eliminate the cancerous stem cells, resulting in lifelong treatments and high risk of relapse. Leukemic stem cells are found mainly in the bone marrow and are protected by the surrounding bone marrow environment, which includes bone, fat, cartilage and blood vessels. There is therefore a great need to identify new drugs targeting the bone marrow environment in order to improve treatment and maintain normal blood formation. This project aims to process the bone marrow environment around the cancer stem cells to reform function and restore it to normal blood formation. The bone marrow environment can indirectly contribute to the development of leukemia by protecting the cancer stem cells against treatment and helping them grow. In our research, we have seen that stromal cells in the bone marrow are altered in CML patients. With modern techniques such as FACS, RNA sequencing and DNA sequencing, as well as preclinical KML and AML mouse models, we want to study how the immediate environment is affected by cancer stem cells and find new strategies to eliminate cancer. Our goal is to identify the cellular and molecular interactions between the cells in the bone marrow environment and the leukemic stem cells, which can contribute to the pathogenesis of leukemia and have significance for the response to treatment. We hope to identify target substances for new targeted drugs that can contribute to better and more effective treatment methods for blood disorders such as KML or AML.

Current treatments for blood cancer are directly targeted at the leukemia cells. Although the majority of leukemias respond well to the initial treatment, drug resistance and relapse are common. Therefore, there is a great need to seek alternative treatments focusing on the stromal cells, which are found in the bone marrow microenvironment around the blood cancer cells, by producing various proteins and molecules protecting the cancer cells from the drugs. In order to identify new treatments, we must understand the role of stromal cells in the bone marrow for the production and maturation of normal blood cells and how they contribute to the development of disease. The bone marrow MSC is one of the stromal cell types and has been shown to interact closely with blood stem cells which then develop into specialized cell types in the blood. But the exact role of MSCs in normal blood flow and blood cancer is unclear. Our goal is to understand how MSC affects the development of disease and identify new disease-related molecules that mediate interaction between MSC and leukemia cells. We will isolate MSC from patients with chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS). The cells are characterized by the latest techniques in flow cytometry, genomic sequencing. The studies will provide important knowledge of how blood formation is affected by the interaction with stromal cells in the bone marrow both under normal conditions and in blood cancer, which may constitute a basis for new stromal cell-targeted treatment strategies for patients with leukemias.

Current treatments for blood cancer are directly targeted at the leukemia cells. Although the majority of leukemias respond well to the initial treatment, drug resistance and relapse are common. Therefore, there is a great need to seek alternative treatments focusing on the stromal cells, which are found in the bone marrow microenvironment around the blood cancer cells, by producing various proteins and molecules protecting the cancer cells from the drugs. In order to identify new treatments, we must understand the role of stromal cells in the bone marrow for the production and maturation of normal blood cells and how they contribute to the development of disease. The bone marrow MSC is one of the stromal cell types and has been shown to interact closely with blood stem cells which then develop into specialized cell types in the blood. But the exact role of MSCs in normal blood flow and blood cancer is unclear. Our goal is to understand how MSC affects the development of disease and identify new disease-related molecules that mediate interaction between MSC and leukemia cells. We will isolate MSC from patients with chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS). The cells are characterized by the latest techniques in flow cytometry, genomic sequencing. The studies will provide important knowledge of how blood formation is affected by the interaction with stromal cells in the bone marrow both under normal conditions and in blood cancer, which may constitute a basis for new stromal cell-targeted treatment strategies for patients with leukemias.

In our bone marrow there are blood cells and stromal cells. Several studies show that stromal cells in the bone marrow can indirectly contribute to blood cancer. The cells do so that the drug against the cancer cells is not effective which increases the risk of the blood cancer coming back. Most treatments today are directed only at the cancer cells, but even if the blood cancer initially responds to treatment, recurrence is common. Furthermore, most of today's cancer drugs cause severe side effects, which is another reason to try to develop treatment methods where the stromal cells are also affected. The exact role of MSC in normal blood flow and blood cancer is still unclear, mainly due to limited knowledge of their normal normal properties. We have, with recently developed methods, in a new way identified cells from mice and humans in bone marrow. We have found that these cells produce a number of substances that are known to be important for blood formation. With our methods we have new opportunities to study the significance of these cells for both blood cancer and normal blood formation. The goal of my studies is to use our new methods to study the function of stromal cells in blood cancer and normal blood formation. We hope that the studies will provide important knowledge of how blood formation is affected by the interaction with stromal cells in the bone marrow both under normal conditions and in blood cancer, which can provide a basis for new treatment strategies for patients with blood cancer.