Lars Rönnstrand- PhD
- Professor (Full) at Lund University
Lars Rönnstrand
- PhD
- Professor (Full) at Lund University
About
304
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Introduction
Current institution
Publications
Publications (304)
Motivation
Missing data present a pervasive challenge in data analysis, potentially biasing outcomes and undermining conclusions if not addressed properly. Missing data are commonly classified into Missing Completely at Random (MCAR), Missing at Random (MAR), and Missing Not at Random (MNAR). While MCAR poses a minimal risk of data distortion, both...
The t(14;19)(q32;q13) is a rare recurring translocation found in B-cell lymphoproliferative malignancies, involving the Bcl-3 gene. This chromosomal translocation is often found in patients under the age of 50 and causes a more progressive disease. The Bcl-3 gene encodes a protein belonging to the IκB family of proteins, which tightly regulates NFκ...
The rapid proliferation of data across diverse fields has accentuated the importance of accurate imputation for missing values. This task is crucial for ensuring data integrity and deriving meaningful insights. In response to this challenge, we present Xputer, a novel imputation tool that adeptly integrates Non-negative Matrix Factorization (NMF) w...
FLT3 emerges as a commonly mutated protein with significant prognostic implications in acute myeloid leukemia (AML). Point mutations or deletions in the tyrosine kinase domain (TKD) at the activation loop and internal tandem duplications (ITD) in the juxtamembrane (JM) region (and less commonly in the TKD) are the primary mutations that occur in th...
Leveraging the potential of machine learning and recognizing the broad applications of binary classification, it becomes essential to develop platforms that are not only powerful but also transparent, interpretable, and user friendly. We introduce alphaML, a user-friendly platform that provides clear, legible, explainable, transparent, and elucidat...
Our understanding of how individual mutations, whether present in all or just a subset of the leukemia cells, affect cellular response to therapy is limited. Herein, we investigate the impact of different therapies on survival, evolution, and resistance patterns in an acute myeloid leukemia (AML) mouse model driven by KMT2A::MLLT3 and subclonal FLT...
The type III receptor tyrosine kinase FLT3 is a pivotal kinase for hematopoietic progenitor cell regulation, with significant implications in acute myeloid leukemia (AML) through mutations like internal tandem duplication (ITD). This study delves into the structural intricacies of FLT3, the roles of activation loop mutants, and their interaction wi...
The type III receptor tyrosine kinase FLT3 is a pivotal kinase for hematopoietic progenitor cell regulation, with significant implications in acute myeloid leukemia (AML) through mutations like internal tandem duplication (ITD). This study delves into the structural intricacies of FLT3, the roles of activation loop mutants, and their interaction wi...
Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends l...
Therapeutic resistance continues to impede overall survival rates for those affected by cancer. Although driver genes are associated with diverse cancer types, a scarcity of instrumental methods for predicting therapy response or resistance persists. Therefore, the impetus for designing predictive tools for therapeutic response is crucial and tools...
Despite incredible progress in cancer treatment, therapy resistance remains the leading limiting factor for long-term survival. During drug treatment, several genes are transcriptionally upregulated to mediate drug tolerance. Using highly variable genes and pharmacogenomic data for acute myeloid leukemia (AML), we developed a drug sensitivity predi...
Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profile selinexor signaling responses using phosphoprote...
Acute myeloid leukemia (AML) is an aggressive form of blood cancer with a poor prognosis. Approximately 30% of AML patients carry mutations in the type III receptor tyrosine kinase FLT3. The most common form of FLT3 mutations includes internal tandem duplication (ITD) mutations, which are also associated with poor clinical outcomes. Several inhibit...
Our understanding of how individual mutations, whether present in all or just a fraction of the leukemia cells, affect cellular responses to therapy is limited. Leukemia mouse models provide a unique possibility to explore how therapy affects the evolution of genetically distinct clones and identify mechanisms of resistance allowing transfer to hum...
Zinc is required for the regulation of proliferation, metabolism, and cell signaling. It is an intracellular second messenger, and the cellular level of ionic, mobile zinc is strictly controlled by zinc transporters. In mammals, zinc homeostasis is primarily regulated by ZIP and ZnT zinc transporters. The importance of these transporters is undersc...
FLT3 is a receptor tyrosine kinase (RTK) that is mutated and constitutively active in 30% of patients with acute myeloid leukemia (AML). Notably, mutations in FLT3 serve as poor prognostic indicator in AML patients. Despite its clinical relevance, the mechanisms of FLT3 subcellular trafficking remain poorly understood. Apart from the canonical down...
Colorectal cancer (CRC) is the third most prevalent cancer worldwide causing an estimated 700000 deaths annually. Different types of treatment are available for patients with advanced metastatic colorectal cancer (mCRC), including targeted biological agents, such as cetuximab, a monoclonal antibody that targets EGFR. We have previously reported a s...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase that is expressed almost exclusively in the hematopoietic compartment. Its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. Activation of FLT3 leads to its autophosphorylation and initiation of several signal transduction cascades...
The receptor tyrosine kinase FLT3 is expressed almost exclusively in the hematopoietic compartment. Binding of its ligand, FLT3 ligand (FL), induces dimerization and activation of its intrinsic tyrosine kinase activity. This leads to autophosphorylation of FLT3 on several tyrosine residues which constitute high affinity binding sites for signal tra...
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Aberrant activation of anaplastic lymphoma kinase (ALK) can cause sporadic and familial neuroblastoma. Using a proteomics approach, we identified Bruton’s tyrosine kinase (BTK) as a novel ALK interaction partner, and the physical interaction was confirmed by co-immunoprecipitation. BTK is expressed in neuroblastoma cell lines and tumor tissues. Its...
The type III receptor tyrosine kinase FLT3 plays important roles in the development of early hematopoietic progenitor cells and is found to be mutated in around 35% of all cases of acute myeloid leukemia (AML). AML is a heterogeneous disease that affects the myeloid lineage of blood cells. Wild-type FLT3 needs its ligand, FL, for signal transductio...
In order to investigate the molecular mechanisms by which the oncogenic mutant KIT/D816V causes transformation of cells, we investigated proteins that selectively bind KIT/D816V, but not wild-type KIT, as potential mediators of transformation. By mass spectrometry several proteins were identified, among them a previously uncharacterized protein den...
Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3 ITD , FLT3 N676K , and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Fur...
Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for a large number of leukemia-related deaths. Mutations in FMS-like tyrosine kinase 3 (FLT3) is one of the most prevalent findings in this heterogeneous disease. The major types of mutations in FLT3 can be categorized as internal tandem duplicatio...
KIT is a receptor tyrosine kinase (RTK) involved in several cellular processes such as regulation of proliferation, survival and differentiation of early hematopoietic cells, germ cells and melanocytes. Activation of KIT results in phosphorylation of tyrosine residues in the receptor, and recruitment of proteins that mediate downstream signaling an...
The non-receptor tyrosine kinase LCK belongs to the SRC family of kinases. SRC family kinases are proto-oncogenes that have long been known to play key roles in cell proliferation, motility, morphology and survival. Here we show that LCK regulates the function of the type III receptor tyrosine kinase FLT3 in murine pro-B cells. We observed that exp...
The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the...
Acute myeloid leukemia (AML) remains the most common form of acute leukemia among adults and accounts for a large number of deaths. Mutation in FMS-like tyrosine kinase 3 (FLT3) is one of the most prevalent factor in this heterogeneous disease. The major mutations in FLT3 can be categories as internal tandem duplications (ITD) and point mutations....
Type III receptor tyrosine kinases (RTKs) including FLT3 and KIT play a major role in cell differentiation, proliferation, and survival of hematopoietic stem cells. FLT3-ITD and KIT-D816V mutations are the most common oncogenic mutations in FLT3 and KIT found in hematological cancers. These mutations lead to constitutive activation of proliferative...
D816V is the most often occurred mutation of type III receptor tyrosine kinase KIT in mastocytosis and CBF-AML. In attempting to identify specific downstream signaling pathways of KIT/D816V, we found that KIT/D816V but not wild-type KIT can bind to Xkr5 that was not studied previously. In addition to the association with KIT/D816V, Xkr5 is phosphor...
Acute myeloid leukemia (AML) is a heterogeneous disease of the blood. About 30 % of AML patients carry an oncogenic mutant of the type III receptor tyrosine kinase FLT3. Among the various mutations in FLT3, the internal tandem duplication (ITD) mutations in the juxtamembrane domain are the most common type of mutation, while point mutations in the...
SRMS (Src-related tyrosine kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites) belongs to a family of non-receptor tyrosine kinases, which harbours a Src homology 3 and a Src homology 2, as well as a protein kinase domain. SRMS was first identified in a screen for the genes that regulate the growth and differentiation...
The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD816V induces tyrosine phosphorylation of MITF through a triple protein complex formation be...
The type III receptor tyrosine kinase FLT3 is one of the most commonly mutated oncogenes in acute myeloid leukemia (AML). Inhibition of mutated FLT3 in combination with chemotherapy has displayed promising results in clinical trials. However, one of the major obstacles in targeting FLT3 is the development of resistant disease due to secondary mutat...
The receptor tyrosine kinase FLT3 is found to be a mutated oncogene in hematological malignancies including acute myeloid leukemia (AML). FLT3 inhibitors in combination with chemotherapy display promising results in a clinical setting, but patients relapse after short-term treatment due to the development of resistant disease. Therefore, targeting...
Up to 30% of patients with acute myeloid leukemia (AML) harbor a mutation in FMS like tyrosine kinase 3 (FLT3). This mutation is not only the most frequent, but also the most clinically challenging, because it is associated with increased risk of relapse and poor overall survival. The most common oncogenic FLT3 mutation is the internal tandem dupli...
The receptor tyrosine kinase FLT3 is mutated in around 30% of acute myeloid leukemia patients. The so-called internal tandem duplication (ITD) mutation in the juxtamembrane domain is the most common type of mutation in FLT3. Other oncogenic mutations include point mutations in the kinase domain. One of the hallmark of receptor activation is phospho...
Fms-like tyrosine kinase (FLT3) is a frequently mutated oncogene in acute myeloid leukemia (AML). FLT3 inhibitors display promising results in a clinical setting, but patients relapse after short-term treatment due to the development of resistant disease. Therefore, a better understanding of FLT3 downstream signal transduction pathways will help to...
The oncogenic D816V mutation of the KIT receptor is well characterized in systemic mastocytosis and acute myeloid leukemia. Although KITD816V has been found in melanoma, its function and involvement in this malignancy is not understood. Here we show that KITD816V induces tyrosine phosphorylation of the microphthalmia-associated transcription factor...
FYN is a non-receptor tyrosine kinase belonging to the SRC family of kinases. SRC family kinases are frequently over-expressed in human cancers, and play key roles in cancer cell invasion, metastasis, proliferation, survival and many other biological processes. SRC has long been recognized as an important oncogene; but little attention has been giv...
Activating mutations in FLT3 occur in up to 35% of patients with AML and correlate with poor prognosis. Therapy directed against FLT3 has been shown to induce response in patients with AML, but these responses are almost always transient. Dual PI3K/mTOR inhibitors have displayed promising results in the treatment of solid tumors, and of hematologic...
Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry...
GADS is a member of a family of SH2 and SH3 domain-containing adaptors that functions in tyrosine kinase-mediated signaling cascades. Its expression is largely restricted to hematopoietic tissues and cell lines. Therefore, GADS is mainly involved in leukocyte-specific protein tyrosine kinase signaling. GADS is known to interact with tyrosine-phosph...
The majority of breast cancers express estrogen receptor α (ERα), and most patients with ERα-positive breast cancer benefit from antiestrogen therapy. The ERα-modulator tamoxifen and ERα-downregulator fulvestrant are commonly employed antiestrogens. Antiestrogen resistance remains a clinical challenge, with few effective treatments available for pa...
FYN is a non-receptor tyrosine kinase belonging to the SRC family of kinases, which are frequently over-expressed in human cancers, and play key roles in cancer biology. SRC has long been recognized as an important oncogene, but little attention has been given to its other family members. In this report, we have studied the role of FYN in FLT3 sign...
Therapy directed against oncogenic FLT3 has been shown to induce response in patients with AML, but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant MV4-11 and MOLM-13 cell lines by sustained treatment with the FLT3 inhibitor sorafenib. MV4-11 cells express only FLT3-ITD,...
The Brain-Expressed X-linked (BEX) family proteins are comprised of five human proteins including BEX1, BEX2, BEX3, BEX4 and BEX5. BEX family proteins are expressed in a wide range of tissues and are known to play a role in neuronal development. Recent studies suggest a role of BEX family proteins in cancers. BEX1 expression is lost in a subgroup o...
