Browsing by keyword "leukemia"
Now showing items 1-11 of 11
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A novel, mitogen-activated nuclear kinase is related to a Drosophila developmental regulatorAlthough the ultimate targets of many signal transduction pathways are nuclear transcription factors, the vast majority of known protein kinases are cytosolic. Here, we report on a novel human kinase that is present exclusively in the nucleus. Kinase activity is increased upon cellular proliferation and is markedly elevated in patients with acute and chronic lymphocytic leukemias. We have identified a human gene that encodes this nuclear kinase and find that it is closely related to Drosophila female sterile homeotic (fsh), a developmental regulator with no known biochemical activity. Collectively, these results suggest that this nuclear kinase is a component of a signal transduction pathway that plays a role in Drosophila development and human growth control.
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Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropeniaNeutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38. The parallel screening of kinase inhibitors revealed that mouse and human neutrophil viability is dependent on cyclin-dependent kinase (CDK) activity but surprisingly only partially dependent on PI3 kinase and JAK/STAT signaling, revealing dominant pathways contributing to neutrophil viability. Mcl-1 haploinsufficiency sensitized neutrophils to CDK inhibition, demonstrating that Mcl-1 is a direct target for CDK inhibitors. This study reveals a therapeutic window for the kinase inhibitors BEZ235, BMS-3, AZD7762, and (R)-BI-2536 to induce apoptosis of leukemia cell lines whilst maintaining immunocompetence and hemostasis.
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Functional Analysis of DNMT3A DNA Methyltransferase Mutations Reported in Patients with Acute Myeloid LeukemiaIn mammals, DNA methylation is necessary for the maintenance of genomic stability, gene expression regulation, and other processes. During malignant diseases progression, changes in both DNA methylation patterns and DNA methyltransferase (MTase) genes are observed. Human de novo MTase DNMT3A is most frequently mutated in acute myeloid leukemia (AML) with a striking prevalence of R882H mutation, which has been extensively studied. Here, we investigate the functional role of the missense mutations (S714C, R635W, R736H, R771L, P777R, and F752V) found in the catalytic domain of DNMT3A in AML patients. These were accordingly mutated in the murine Dnmt3a catalytic domain (S124C, R45W, R146H, R181L, P187R, and F162V) and in addition, one-site CpG-containing DNA substrates were used as a model system. The 3-15-fold decrease (S124C and P187R) or complete loss (F162V, R45W, and R146H) of Dnmt3a-CD methylation activity was observed. Remarkably, Pro 187 and Arg 146 are not located at or near the Dnmt3a functional motives. Regulatory protein Dnmt3L did not enhance the methylation activity of R45W, R146H, P187R, and F162V mutants. The key steps of the Dnmt3a-mediated methylation mechanism, including DNA binding and transient covalent intermediate formation, were examined. There was a complete loss of DNA-binding affinity for R45W located in the AdoMet binding region and for R146H. Dnmt3a mutants studied in vitro suggest functional impairment of DNMT3A during pathogenesis.
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Imaging Musculoskeletal Manifestations of Pediatric Hematologic MalignanciesOBJECTIVE. The purpose of this article is to describe imaging findings of common and uncommon musculoskeletal manifestations, posttreatment changes, and complications of pediatric hematologic malignancies. CONCLUSION. Many pediatric patients with leukemia and lymphoma present with or experience musculoskeletal symptoms over the course of the disease. Imaging can depict bone and soft-tissue signs of pediatric hematologic malignancies and plays an important role in the diagnosis of complications and treatment-related changes.
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Mitoxantrone-Induced Cardiotoxicity in Acute Myeloid Leukemia-A Velocity Vector Imaging AnalysisBACKGROUND: The purpose of this investigation was to: (1) determine incidence and predictors of mitoxantrone-induced early cardiotoxicity and (2) study left ventricular mechanics before and after receiving mitoxantrone. METHOD AND RESULTS: We retrospectively analyzed 80 subjects diagnosed with acute myeloid leukemia (AML) who underwent chemotherapy with bolus high-dose mitoxantrone. Echocardiographic measurements were taken at baseline and at a median interval of 55 days after receiving mitoxantrone. Thirty-five (44%) of the patients developed clinically defined early cardiotoxicity, 29 (36%) of which developed heart failure. There was a significant decrease in the ejection fraction (EF) not only in the cardiotoxicity group (17.6 +/- 14.8%, P < 0.001) but also in the noncardiotoxicity group (5.3 +/- 8.4%, P < 0.001). Decrease in global longitudinal strain (GLS) (-3.7 +/- 4.5, P < 0.001 vs. -2.4 +/- 4.3, P = 0.01) and global circumferential strain (GCS) (-5.6 +/- 9, P = 0.003 vs. -5.3 +/- 8.7, P < 0.001) was significant in both the cardiotoxicity and noncardiotoxicity group, respectively. A multivariate model including baseline left ventricular end-systolic diameter, baseline pre-E/A ratio, and baseline pre-E/e' ratio was found to be the best-fitted model for prediction of mitoxantrone-induced early clinical cardiotoxicity. CONCLUSION: High-dose mitoxantrone therapy is associated with an excellent remission rate but with a significantly increased risk of clinical and subclinical early cardiotoxicity and heart failure. Mitoxantrone-induced systolic dysfunction is evident from reduction in EF, increase in Tei index, and significant reduction in GLS and GCS. Baseline impaired ventricular relaxation evident from higher E/e' ratio and lower E/A ratio independently predicts increased risk of mitoxantrone-induced early cardiotoxicity.
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Opportunities, barriers, and recommendations in down syndrome researchBACKGROUND: Recent advances in medical care have increased life expectancy and improved the quality of life for people with Down syndrome (DS). These advances are the result of both pre-clinical and clinical research but much about DS is still poorly understood. In 2020, the NIH announced their plan to update their DS research plan and requested input from the scientific and advocacy community. OBJECTIVE: The National Down Syndrome Society (NDSS) and the LuMind IDSC Foundation worked together with scientific and medical experts to develop recommendations for the NIH research plan. METHODS: NDSS and LuMind IDSC assembled over 50 experts across multiple disciplines and organized them in eleven working groups focused on specific issues for people with DS. RESULTS: This review article summarizes the research gaps and recommendations that have the potential to improve the health and quality of life for people with DS within the next decade. CONCLUSIONS: This review highlights many of the scientific gaps that exist in DS research. Based on these gaps, a multidisciplinary group of DS experts has made recommendations to advance DS research. This paper may also aid policymakers and the DS community to build a comprehensive national DS research strategy.
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Preleukemia and Leukemia-Initiating Cell Activity in inv(16) Acute Myeloid LeukemiaAcute myeloid leukemia (AML) is a collection of hematologic malignancies with specific driver mutations that direct the pathology of the disease. The understanding of the origin and function of these mutations at early stages of transformation is critical to understand the etiology of the disease and for the design of effective therapies. The chromosome inversion inv(16) is thought to arise as a founding mutation in a hematopoietic stem cell (HSC) to produce preleukemic HSCs (preL-HSCs) with myeloid bias and differentiation block, and predisposed to AML. Studies in mice and human AML cells have established that inv(16) AML follows a clonal evolution model, in which preL-HSCs expressing the fusion protein CBFbeta-SMMHC persist asymptomatic in the bone marrow. The emerging leukemia-initiating cells (LICs) are composed by the inv(16) and a heterogeneous set of mutations. In this review, we will discuss the current understanding of inv(16) preleukemia development, and the function of CBFbeta-SMMHC related to preleukemia progression and LIC activity. We also discuss important open mechanistic questions in the etiology of inv(16) AML.
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Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR reportThere is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.
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Role of Immunomodulation of BCG Therapy on AML RemissionBacillus Calmette-Guerin (BCG) has been studied in various cancers for its immune modulation. Although the mechanism is yet to be completely understood, we do have positive experiences in many oncological cases. Hereby, we present a case of an 82-year-old male with acute myeloid leukemia (AML) post allogeneic Stem Cell Transplants (AlloSCT) as a salvage therapy, now in remission, who presented with hematuria. Workup confirmed non-muscle invasive Bladder Cancer (NMIBC), for which he was treated with nine sessions of intravesical BCG therapy. During BCG treatment, the patient developed gradually increasing lymphocyte counts. Flowcytometry of a peripheral blood sample showed polyclonal cell lymphocytosis with CD8+ T-cell expansion. Although further work up his lymphocytosis to be polyclonal, it has persisted at follow-up for the last 4 years. Also, we did not find any evidence of leukemia recurrence at follow-up prompting us to associate the BCG use for this patient and it is role as immunomodulation to keep AML disease in remission.
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RUNX1-dependent mechanisms in biological control and dysregulation in cancerThe RUNX1 transcription factor has recently been shown to be obligatory for normal development. RUNX1 controls the expression of genes essential for proper development in many cell lineages and tissues including blood, bone, cartilage, hair follicles, and mammary glands. Compromised RUNX1 regulation is associated with many cancers. In this review, we highlight evidence for RUNX1 control in both invertebrate and mammalian development and recent novel findings of perturbed RUNX1 control in breast cancer that has implications for other solid tumors. As RUNX1 is essential for definitive hematopoiesis, RUNX1 mutations in hematopoietic lineage cells have been implicated in the etiology of several leukemias. Studies of solid tumors have revealed a context-dependent function for RUNX1 either as an oncogene or a tumor suppressor. These RUNX1 functions have been reported for breast, prostate, lung, and skin cancers that are related to cancer subtypes and different stages of tumor development. Growing evidence suggests that RUNX1 suppresses aggressiveness in most breast cancer subtypes particularly in the early stage of tumorigenesis. Several studies have identified RUNX1 suppression of the breast cancer epithelial-to-mesenchymal transition. Most recently, RUNX1 repression of cancer stem cells and tumorsphere formation was reported for breast cancer. It is anticipated that these new discoveries of the context-dependent diversity of RUNX1 functions will lead to innovative therapeutic strategies for the intervention of cancer and other abnormalities of normal tissues.
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YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent mannerRNA-binding proteins (RBPs) are critical regulators of transcription and translation that are often dysregulated in cancer. Although RBPs are increasingly recognized as being important for normal hematopoiesis and for hematologic malignancies as oncogenes or tumor suppressors, RBPs that are essential for the maintenance and survival of leukemia remain elusive. Here we show that YBX1 is specifically required for maintaining myeloid leukemia cell survival in an N6-methyladenosine (m6A)-dependent manner. We found that expression of YBX1 is significantly upregulated in myeloid leukemia cells, and deletion of YBX1 dramatically induces apoptosis and promotes differentiation coupled with reduced proliferation and impaired leukemic capacity of primary human and mouse acute myeloid leukemia cells in vitro and in vivo. Loss of YBX1 has no obvious effect on normal hematopoiesis. Mechanistically, YBX1 interacts with insulin-like growth factor 2 messenger RNA (mRNA)-binding proteins (IGF2BPs) and stabilizes m6A-tagged RNA. Moreover, YBX1 deficiency dysregulates the expression of apoptosis-related genes and promotes mRNA decay of MYC and BCL2 in an m6A-dependent manner, which contributes to the defective survival that results from deletion of YBX1. Thus, our findings have uncovered a selective and critical role of YBX1 in maintaining myeloid leukemia survival, which might provide a rationale for the therapeutic targeting of YBX1 in myeloid leukemia.
