scholarly journals Germline Genetic Predisposition to Hematologic Malignancy

2017 ◽  
Vol 35 (9) ◽  
pp. 1018-1028 ◽  
Author(s):  
Elissa Furutani ◽  
Akiko Shimamura
Keyword(s):  
Hematologic Malignancy ◽  
Treatment Strategies ◽  
Hematologic Malignancies ◽  
Genomic Testing ◽  
Hematopoietic Stem ◽  
Sequencing Technologies ◽  
Prognostic Stratification ◽  
Risk Of Treatment ◽  
Choice Of Therapy

Development of hematologic malignancies is driven by mutations that may be somatic or germline. Availability of next-generation DNA sequencing technologies has facilitated the development of individualized diagnostic evaluations and tailored treatment strategies. Until now, such personalized medical approaches have largely centered on prognostic stratification and treatment strategies informed by acquired somatic mutations. The role of germline mutations in children and adults with hematologic malignancies was previously underappreciated. Diagnosis of an inherited predisposition to hematologic malignancy informs choice of therapy, risk of treatment-related complications, donor selection for hematopoietic stem cell transplantation, evaluation of comorbidities, and surveillance strategies to improve clinical outcomes. The recognition that patients with inherited hematologic malignancy syndromes may present without classic clinical stigmata or suspicious family history has led to increased reliance on genetic testing, which, in turn, has raised new diagnostic challenges. Genomic testing is a rapidly evolving field with an increasing number of choices for testing for the practicing clinician to navigate. This review will discuss general approaches to diagnosis and management of patients with germline predisposition to hematology malignancies and will consider applications and limitations of genomic testing in clinical practice.

scholarly journals Epigenetic targeting and personalized approaches for AML

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 44-51 ◽  
Author(s):  
Gail J. Roboz
Keyword(s):  
Molecular Genetic ◽  
Treatment Strategies ◽  
Regulation Of Transcription ◽  
Hematopoietic Stem ◽  
Genetic Characteristics ◽  
Sequencing Technologies ◽  
Recurrent Mutations ◽  
Genes Encoding ◽  
Cell Disorder

Abstract Acute myeloid leukemia (AML) is a genetically heterogeneous clonal hematopoietic stem cell disorder and the majority of patients with AML die from their disease. The treatment paradigms for AML were developed decades ago and, although there have been improvements in the outcomes of selected younger patients and those with specific cytogenetic and molecular genetic characteristics, the overall survival for older patients remains dismal. Over the last few years, next-generation sequencing technologies have identified recurrent mutations in genes encoding proteins involved in the epigenetic regulation of transcription in most patients with AML. This discovery has led to new insights into the role of the epigenome in AML and opens the possibility of epigenetically targeted therapies. This chapter describes how epigenetic dysregulation plays a role in AML and highlights current and future treatment strategies that attempt to exploit epigenetic targets.

scholarly journals Autophagy and Metabolism in Normal and Malignant Hematopoiesis

2021 ◽  
Vol 22 (16) ◽  
pp. 8540
Author(s):  
Ioanna E. Stergiou ◽  
Efstathia K. Kapsogeorgou
Keyword(s):  
Hematopoietic Cells ◽  
Building Blocks ◽  
Hematologic Malignancies ◽  
Mitochondrial Content ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Regulation Of Metabolism ◽  
Multipotent Differentiation

The hematopoietic system relies on regulation of both metabolism and autophagy to maintain its homeostasis, ensuring the self-renewal and multipotent differentiation potential of hematopoietic stem cells (HSCs). HSCs display a distinct metabolic profile from that of their differentiated progeny, while metabolic rewiring from glycolysis to oxidative phosphorylation (OXPHOS) has been shown to be crucial for effective hematopoietic differentiation. Autophagy-mediated regulation of metabolism modulates the distinct characteristics of quiescent and differentiating hematopoietic cells. In particular, mitophagy determines the cellular mitochondrial content, thus modifying the level of OXPHOS at the different differentiation stages of hematopoietic cells, while, at the same time, it ensures the building blocks and energy for differentiation. Aberrations in both the metabolic status and regulation of the autophagic machinery are implicated in the development of hematologic malignancies, especially in leukemogenesis. In this review, we aim to investigate the role of metabolism and autophagy, as well as their interconnections, in normal and malignant hematopoiesis.

HLA mismatch combinations associated with decreased risk of relapse: implications for the molecular mechanism

Blood ◽  
2009 ◽  
Vol 113 (12) ◽  
pp. 2851-2858 ◽  
Author(s):  
Takakazu Kawase ◽  
Keitaro Matsuo ◽  
Koichi Kashiwase ◽  
Hidetoshi Inoko ◽  
Hiroh Saji ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Hematologic Malignancy ◽  
Human Leukocyte ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Clinical Issue ◽  
Leukocyte Antigen ◽  
Unrelated Donors ◽  
Risk Of Relapse ◽  
Made In

Abstract The finding that the risk of relapse in hematologic malignancy decreases after allogeneic hematopoietic stem cell transplantation (HSCT) has lead to the concept of a graft-versus-leukemia (GVL) effect. However, this beneficial effect is considered to be frequently offset by graft-versus-host disease (GVHD). Thus, improving HSCT outcomes by separating GVL from GVHD is a key clinical issue. This cohort study registered 4643 patients with hematologic malignancies who received transplants from unrelated donors. Six major human leukocyte antigen (HLA) loci were retrospectively genotyped. We identified 4 HLA-Cw and 6 HLA-DPB1 mismatch combinations responsible for a decreased risk of relapse; of these, 8 of 10 combinations were different from those responsible for severe acute GVHD, including all 6 of the HLA-DPB1 combinations. Pairs with these combinations of HLA-DPB1 were associated with a significantly better overall survival than were completely matched pairs. Moreover, several amino acid substitutions on specific positions responsible for a decreased risk of relapse were identified in HLA-Cw, but not in HLA-DPB1. These findings might be crucial to elucidating the mechanism of the decreased risk of relapse on the basis of HLA molecule. Donor selection made in consideration of these results might allow the separation of GVL from acute GVHD, especially in HLA-DPB1 mismatch combinations.

scholarly journals The possible role of mutated endothelial cells in myeloproliferative neoplasms

Haematologica ◽  
2021 ◽  
Author(s):  
Mirko Farina ◽  
Domenico Russo ◽  
Ronald Hoffman
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Hematopoietic Cells ◽  
Clinical Manifestations ◽  
Vascular Complications ◽  
Hematologic Malignancies ◽  
Driver Mutations ◽  
Vascular Events ◽  
Hematopoietic Stem ◽  
High Incidence

Myeloproliferative neoplasms (MPN) are chronic, clonal hematologic malignancies characterized by myeloproliferation and a high incidence of vascular complications (thrombotic and bleeding). Although MPN-specific driver mutations have been identified, the underlying events that culminate in these clinical manifestations require further clarification. We reviewed the numerous studies performed during the last decade identifying endothelial cell (EC) dysregulation as a factor contributing to MPN disease development. The JAK2V617F MPN mutation and other myeloid-associated mutations have been detected not only in hematopoietic cells but also in EC and their precursors in MPN patients, suggesting a link between mutated EC and the high incidence of vascular events. To date, however, the role of EC in MPN continues to be questioned by some investigators. In order to further clarify the role of EC in MPN, we first describe the experimental strategies used to study EC biology and then analyze the available evidence generated using these assays which implicate mutated EC in MPN-associated abnormalities. Mutated EC have been reported to possess a pro-adhesive phenotype as a result of increased endothelial Pselectin exposure, secondary to degranulation of Weibel-Palade bodies, which is further accentuated by exposure to pro-inflammatory cytokines. Additional evidence indicates that MPN myeloproliferation requires JAK2V617F expression by both hematopoietic stem cells and EC. Furthermore, the reports of JAK2V617F and other myeloid malignancy- associated mutations in both hematopoietic cells and EC in MPN patients support the hypothesis that MPN driver mutations may first appear in a common precursor cell for both EC and hematopoietic cells.

Role of STAT3 in Immunoregulatory Function of Human Bone Marrow-Derived Mesenchymal Stem Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3637-3637
Author(s):  
Jinsun Yoon ◽  
Seoju Kim ◽  
Eun Shil Kim ◽  
Byoung Kook Kim ◽  
Young Lee
Keyword(s):  
T Cells ◽  
Conflicts Of Interest ◽  
Hematologic Malignancies ◽  
Treg Cells ◽  
Human Mscs ◽  
Hematopoietic Stem ◽  
The One

Abstract Abstract 3637 Poster Board III-573 The one of the best curative treatment modality in hematologic malignancies is an allogeneic hematopoietic stem cell transplantation (HSCT). However, graft-versus-host disease (GVHD) is a major obstacle of allogeneic HSCT. BM derived human MSCs are known to have immunoregulatory effect in vitro and in vivo via inhibiting alloreactive T lymphocytes, leading to their clinical use for the prevention of GVHD in HSCT. However, the molecular mechanism of immunoregulatory effect of human MSCs is not fully understood. In this study, the signaling of immunoregulatory effect was investigated by co-culture of human MSCs with lymphocytes. The proliferation of allogeneic T cells was inhibited by MSCs. Among the STATs, STAT3 was a key molecule in MLR co-cultured with MSCs. STAT3 siRNA treated MSCs did not inhibit the lymphocyte proliferation. After MSCs were trasnsfected with STAT3 plasmid, the fraction of CD4+CD25+FOXP3+ cells (Treg cells) were increased, while the fraction of CD4+, CD8+, CD25+ was decreased. In addition, Th1-related cytokines (IL-2, IL-12 and INF-γ) and Th17-related cytokines (IL-6, IL-17 and IL-21) were down-regulated, and Th2-related cytokines (GATA-3, IL-4 and IL-10) were up-regulated in MLR co-cultured with STAT3-ablated MSCs, while vice versa in MLR co-cultured with STAT3-transfected MSCs. Furthermore, ELISA showed that concentration of Th1-related cytokine (IL-2) in the supernatant of MLR co-cultured with STAT3-ablated MSCs was higher than that of control; while concentration of Th2-related cytokine (IL-4) was lower than that of control. These results suggested that induction of Th1 to Th2 shift by MSCs might be mediated via STAT3 molecule. In summary, STAT3 may be an indispensable molecule in the immunoregulatory effect in human MSCs via modulation of regulatory T cells. Disclosures: No relevant conflicts of interest to declare.

Adiponectin as a biomarker linking obesity and adiposopathy to hematologic malignancies

2015 ◽  
Vol 23 (1) ◽  
Author(s):  
Maria Dalamaga ◽  
Gerasimos S. Christodoulatos
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Inflammatory Responses ◽  
Direct Action ◽  
Hematologic Malignancies ◽  
Target Tissue ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Hematopoietic Cancer

AbstractHigher body mass index and adiposopathy have been associated with increased risk of hematologic malignancies such as leukemia, multiple myeloma, myeloproliferative disorders, Hodgkin’s and non-Hodgkin’s lymphoma, and myelodysplastic syndromes. Adiponectin is a multimeric protein of the white adipose tissue presenting anti-inflammatory, insulin-sensitizing, anti-atherogenic, cardioprotective, and anti-neoplastic properties. Its anti-neoplastic actions are manifested via two mechanisms: (i) direct action on tumor cells by enhancing receptor-mediated signaling pathways and (ii) indirect action by regulating inflammatory responses, influencing cancer angiogenesis, and modulating insulin sensitivity at the target tissue site. In the bone marrow milieu, adiponectin and its main receptors are expressed by the majority of bone marrow stromal cell populations influencing hematopoietic stem cells function. Adiponectin may represent a molecular mediator relating adiposopathy with leukemogenesis and myelomagenesis. Several epidemiological studies conducted to date relate hypoadiponectinemia to the risk of myeloid-derived hematopoietic cancer and multiple myeloma. Adiponectin may be a promising biomarker with potential diagnostic and prognostic utility in determining the likelihood of myeloma and leukemia progression in certain cohorts of monoclonal gammopathy of undetermined significance patients and in myeloid hematologic malignancies, respectively. This review summarizes experimental and epidemiologic data regarding the role of adiponectin in hematologic malignancies in the context of adiposopathy. Enhancement of endogenous adiponectin, adiponectin replacement, or manipulation of adiponectin receptor sensitivity may be an attractive goal for prevention and an effective therapeutic strategy against hematopoietic cancer, specifically in overweight/obese individuals. Further studies are required to elucidate the role of the bone marrow microenvironment adiponectin in complex interactions involved in preleukemic and leukemic states.

scholarly journals Newly Found Peacekeeper: Potential of CD8+ Tregs for Graft-Versus-Host Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Weihao Wang ◽  
Tao Hong ◽  
Xiaoqi Wang ◽  
Rui Wang ◽  
Yuxuan Du ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cellular Therapy ◽  
Hematologic Malignancies ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cytokine Levels ◽  
Underlying Mechanisms ◽  
Clinical Advances

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most effective and potentially curative treatment for a variety of hematologic malignancies. However, graft-versus-host disease (GVHD) is a major obstacle that limits wide application of allo-HSCT, despite the development of prophylactic strategies. Owing to experimental and clinical advances in the field, GVHD is characterized by disruption of the balance between effector and regulatory immune cells, resulting in higher inflammatory cytokine levels. A reduction in regulatory T cells (Tregs) has been associated with limiting recalibration of inflammatory overaction and maintaining immune tolerance. Moreover, accumulating evidence suggests that immunoregulation may be useful for preventing GVHD. As opposed to CD4+ Tregs, the CD8+ Tregs population, which constitutes an important proportion of all Tregs, efficiently attenuates GVHD while sparing graft-versus-leukemic (GVL) effects. CD8+ Tregs may provide another form of cellular therapy for preventing GVHD and preserving GVL effects, and understanding the underlying mechanisms that different from those of CD4+ Tregs is significant. In this review, we summarize preclinical experiments that have demonstrated the role of CD8+ Tregs during GVHD and attempted to obtain optimized CD8+ Tregs. Notably, although optimized CD8+ Tregs have obvious advantages, more exploration is needed to determine how to apply them in the clinic.

scholarly journals Determining the role of inflammation in the selection of JAK2 mutant cells in myeloproliferative neoplasms

2016 ◽  
Author(s):  
Jie Zhang ◽  
Angela Fleischman ◽  
Dominik Wodarz ◽  
Natalia L. Komarova
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Hematologic Malignancy ◽  
Clonal Evolution ◽  
Myeloproliferative Neoplasm ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Evolutionary Advantage ◽  
Functional Forms ◽  
Mutant Cells

AbstractMyeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2V 617F). This mutation endows upon myeloid progenitors cytokine independent growth and consequently leads to excessive production of myeloid lineage cells. It has been previously suggested that inflammation may play a role in the clonal evolution of JAK2V 617F mutants. In particular, it is possible that one or more cellular kinetic parameters of hematopoietic stem cells (HSCs) are affected by inflammation, such as division or death rates of cells, and the probability of HSC differentiation. This suggests a mechanism that can steer the outcome of the cellular competition in favor of the mutants, initiating the disease. In this paper we create a number of mathematical evolutionary models, from very abstract to more concrete, that describe cellular competition in the context of inflammation. It is possible to build a model axiomatically, where only very general assumptions are imposed on the modeling components and no arbitrary (and generally unknown) functional forms are used, and still generate a set of testable predictions. In particular, we show that, if HSC death is negligible, the evolutionary advantage of mutant cells can only be conferred by an increase in differentiation probability of HSCs in the presence of inflammation, and if death plays a significant role in the dynamics, an additional mechanism may be an increase of HSC’s division-to-death ratio in the presence of inflammation. Further, we show that in the presence of inflammation, the wild type cell population is predicted to shrink under inflammation (even in the absence of mutants). Finally, it turns out that if only the differentiation probability is affected by the inflammation, then the resulting steady state population of wild type cells will contain a relatively smaller percentage of HSCs under inflammation. If the division-to-death rate is also affected, then the percentage of HSCs under inflammation can either decrease or increase, depending on other parameters.

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