Browsing by Subject "Myeloid leukemia"

Now showing 1 - 3 of 3
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    Multiple Organ Dysfunction and Critically Ill Children with Acute Myeloid Leukemia: single-center retrospective cohort study
    (Wolters Kluwer, 2023) Gaugler, Mary; Swinger, Nathan; Rahrig, April L.; Skiles, Jodi; Rowan, Courtney M.; Pediatrics, School of Medicine
    Objectives: To describe the prevalence of multiple organ dysfunction syndrome (MODS) and critical care utilization in children and young adults with acute myeloid leukemia (AML) who have not undergone hematopoietic cell transplantation (HCT). Design: Retrospective cohort study of MODS (defined as dysfunction of two or more organ systems) occurring any day within the first 72 hours of PICU admission. Setting: Large, quaternary-care children's hospital. Patients: Patients 1 month through 26 years old who were treated for AML from 2011-2019. Interventions: None. Measurements and main results: Eighty patients with AML were included. These 80 patients had a total of 409 total non-HCT-related hospital and 71 PICU admissions. The majority 53 of 71 of PICU admissions (75%) were associated with MODS within the first 72 hours. MODS was present in 49 of 71 of PICU admissions (69%) on day 1, 29 of 52 (56%) on day 2, and 25 of 32 (78%) on day 3. The organ systems most often involved were hematologic, respiratory, and cardiovascular. There was an increasing proportion of renal failure (8/71 [11%] on day 1 to 8/32 [25%] on day 3; p = 0.02) and respiratory failure (33/71 [47%] to 24/32 [75%]; p = 0.001) as PICU stay progressed. The presence of MODS on day 1 was associated with a longer PICU length of stay (LOS) (β = 5.4 [95% CI, 0.7-10.2]; p = 0.024) and over a six-fold increased risk of an LOS over 2 days (odds ratio, 6.08 [95% CI, 1.59-23.23]; p = 0.008). Respiratory failure on admission was associated with higher risk of increased LOS. Conclusions: AML patients frequently require intensive care. In this cohort, MODS occurred in over half of PICU admissions and was associated with longer PICU LOS. Respiratory failure was associated with the development of MODS and progressive MODS, as well as prolonged LOS.
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    Role of S6K1 in regulating self-renewal of hematopoietic stem cells and propagatoin of leukemia
    (2015-12-15) Ghosh, Joydeep; Kapur, Reuben; Carlesso, Nadia; Pelus, Louis M.; Srour, Edward F.
    The development and function of hematopoietic stem cells (HSCs) is regulated by numerous signaling pathways including Akt-mechanistic target of rapamycin complex1 (mTORC1) pathway. Dysregulation of this pathway results in impaired HSC function and contributes to the development of hematologic malignancies. Activated mTORC1 phosphorylates and subsequently activates ribosomal protein S6 kinase 1 (S6K1). To study the role of S6K1 in hematopoiesis as well as leukemogenesis, we used a genetic model of S6K1 deficient mice (S6K1-/-). We found that loss of S6K1 expression in HSCs results in reduction of absolute HSC number in bone marrow (BM). Following chemotherapy, cycling HSCs undergo apoptosis and quiescent HSCs are required to cycle to regenerate the hematopoietic system. S6K1 regulates the quiescence of HSCs and in the absence of S6K1, mice are more susceptible to repeated myeloablative stress. We also observed that loss of expression as well as gain of expression of S6K1 affects the self-renewal ability of HSCs. Interestingly, when we overexpressed S6K1, it also resulted in reduced self-renewal of HSCs. Next, we assessed the role of S6K1 in the propagation of acute myeloid leukemia (AML). The mixed-lineage leukemia (MLL) gene is required for the maintenance of adult HSCs. Translocations in MLL are detected in approximately 5-10% of adult acute leukemia patients and in approximately 70% of acute leukemias in infants. We expressed MLL-AF9 fusion oncoprotein in WT and S6K1-/- hematopoietic stem and progenitor cells (HSC/Ps) and performed serial transplantation. Upon secondary transplantation, recipients of S6K1 deficient AML cells survived significantly longer compared to controls. In vitro, pharmacological inhibition of S6K1 activity resulted in reduced growth of primary human cells expressing MLL-AF9. Both human and murine HSC/Ps expressing MLL-AF9 showed reduced mTORC1 activity upon inhibition of S6K1 suggesting that loss of S6K1 activity results in reduced Akt-mTORC1 activation both upstream and downstream of mTORC1. Overall, our studies establish a critical role of S6K1 activity in the maintenance of HSC function and in the propagation of leukemia.
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    The impact of obesity-induced inflammation on clonal hematopoiesis
    (Wolters Kluwer, 2024) Pasupuleti, Santhosh Kumar; Kapur, Reuben; Pediatrics, School of Medicine
    Purpose of review: This review meticulously delves into existing literature and recent findings to elucidate the intricate link between obesity and clonal hematopoiesis of indeterminate potential (CHIP) associated clonal hematopoiesis. It aims to enhance our comprehension of this multifaceted association, offering insights into potential avenues for future research and therapeutic interventions. Recent findings: Recent insights reveal that mutations in CHIP-associated genes are not limited to symptomatic patients but are also present in asymptomatic individuals. This section focuses on the impact of obesity-induced inflammation and fatty bone marrow (FBM) on the development of CHIP-associated diseases. Common comorbidities such as obesity, diabetes, and infection, fostering pro-inflammatory environments, play a pivotal role in the acceleration of these pathologies. Our research underscores a notable association between CHIP and an increased waist-to-hip ratio (WHR), emphasizing the link between obesity and myeloid leukemia. Recent studies highlight a strong correlation between obesity and myeloid leukemias in both children and adults, with increased risks and poorer survival outcomes in overweight individuals. Summary: We discuss recent insights into how CHIP-associated pathologies respond to obesity-induced inflammation, offering implications for future studies in the intricate field of clonal hematopoiesis.