Blood Stem Cell and Hematological Malignancies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 30 November 2024 | Viewed by 4496

Special Issue Editor


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Guest Editor
1. Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
2. Department of Pathology and Laboratory Medicine, The University of Tennessee, Memphis, TN 38163, USA
Interests: hematopoietic stem and progenitor cells; single-cell dynamics; cell fate decisions; asymmetric cell division; cell polarity; lysosomes; mitochondria

Special Issue Information

Dear Colleagues,

Hematopoietic stem cells (HSCs) are critical for the lifelong production of blood. This rare, tissue-specific stem cell resides in the bone marrow, promoting the release of mature blood cells and self-renewing to produce novel HSCs. Because of their unique properties, HSCs are the foundation of regenerative medicine and are used to reconstitute the entire hematopoietic system in hematopoietic stem cell transplants. Once transplanted, hematopoietic stem cells replace or complement the hematopoietic system in patients, a process which is often the only curative therapy for many blood diseases. While HSCs can cure diseases, many hematological diseases begin with mutations in HSCs. Mutations in HSCs can provide a fitness advantage, allowing mutant HSCs to outcompete their normal counterparts over time. Competition between different HSC clones leads to subtle changes in hematopoiesis at first and accelerates with time as mutant HSC clones expand and acquire additional mutations. Although clonal evolution ultimately drives the progression of every disease, the process itself is still poorly understood. A better understanding of hematopoietic stem cell biology in health and disease is thus needed to prevent and delay clonal evolution, limit disease progression, and develop better treatments.

In this Special Issue, we are pleased to invite you to contribute your latest findings, share exciting novel insights, and summarize the current research of your field of research. This Special Issue aims to highlight recent research advances in hematopoietic stem cell biology, including their role in hematological malignancies, clonal hematopoiesis, myelodysplastic syndromes, and the part played by cell-intrinsic vs. cell-extrinsic factors in disease progression. In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following areas:

  • Hematopoietic stem cells;
  • Clonal hematopoiesis;
  • Hematological malignancies;
  • Bone marrow failures;
  • Translational research.

We look forward to receiving your contributions.

Dr. DIrk Loeffler
Guest Editor

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Keywords

  • hematopoietic stem cells
  • hematological malignancies
  • clonal hematopoiesis
  • clonal evolution
  • preleukemia and leukemia
  • self-renewal and differentiation
  • asymmetric cell division
  • cell polarity
  • therapy resistance
  • transformation

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Published Papers (4 papers)

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Research

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16 pages, 721 KiB  
Article
Improved Outcomes in Myelofibrosis after Allogeneic Stem-Cell Transplantation in the Era of Ruxolitinib Pretreatment and Intensified Conditioning Regimen—Single-Center Analysis
by Sigrid Machherndl-Spandl, Sarah Hannouf, Alexander Nikoloudis, Otto Zach, Irene Strassl, Emine Kaynak, Gerald Webersinke, Christine Gruber-Rossipal, Holger Rumpold, Wolfgang Schimetta, Johannes Clausen and Veronika Buxhofer-Ausch
Cancers 2024, 16(19), 3257; https://doi.org/10.3390/cancers16193257 - 25 Sep 2024
Viewed by 861
Abstract
(1) Background: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the only treatment with the potential for cure in patients with myelofibrosis (MF). However, the risk of graft rejection, which is particularly high in MF, and the risk of significant non-relapse mortality must be considered. [...] Read more.
(1) Background: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is the only treatment with the potential for cure in patients with myelofibrosis (MF). However, the risk of graft rejection, which is particularly high in MF, and the risk of significant non-relapse mortality must be considered. (2) Methods: In this retrospective, single-center study, we compared allo-HSCT outcomes in 36 adult patients with MF transplanted at two-time intervals (2001–2015 versus 2016–2021). (3) Results: The estimated median overall survival was 48.9 months (95%CI 0.00–98.2) in the cohort transplanted before 2016 and not reached in the more recent years (p = 0.04) due to markedly lower non-relapse mortality (p = 0.02). The 3-year relapse incidence was low in both cohorts (11.1% and 12.5%, p > 0.99). When comparing only subgroups within the more recent cohort based on the presence or absence of total body irradiation (TBI) or the use of sequential regimens, OS and PFS were comparable. (4) Conclusion: Pretreatment with ruxolitinib, intensified conditioning, and the preferential use of haploidentical related instead of mismatched unrelated donors for patients lacking an HLA-identical donor are most likely responsible for the improved outcome after allo-HCT in MF in recent years. Full article
(This article belongs to the Special Issue Blood Stem Cell and Hematological Malignancies)
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12 pages, 1753 KiB  
Article
The Leukemic Isocitrate Dehydrogenase (IDH) 1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs)
by Sara Pierangeli, Serena Donnini, Valerio Ciaurro, Francesca Milano, Valeria Cardinali, Sofia Sciabolacci, Gaetano Cimino, Ilaria Gionfriddo, Roberta Ranieri, Sabrina Cipriani, Eleonora Padiglioni, Roberta Iacucci Ostini, Tiziana Zei, Antonio Pierini and Maria Paola Martelli
Cancers 2024, 16(15), 2675; https://doi.org/10.3390/cancers16152675 - 27 Jul 2024
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Abstract
How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase (IDH) gene mutations in the human model of HSPC [...] Read more.
How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase (IDH) gene mutations in the human model of HSPC and discuss the available literature on this topic. IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on HSPCs, we expressed IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells via lentiviral transduction and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by specific inhibitors, confirming that it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission. Full article
(This article belongs to the Special Issue Blood Stem Cell and Hematological Malignancies)
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12 pages, 549 KiB  
Article
Development and Validation of a Concise Objectifiable Risk Evaluation Score for Non-Relapse Mortality after Allogeneic Hematopoietic Stem Cell Transplantation
by Gunnar Weise, Radwan Massoud, Rolf Krause, Silke Heidenreich, Dietlinde Janson, Evgeny Klyuchnikov, Christine Wolschke, Gaby Zeck, Nicolaus Kröger and Francis Ayuk
Cancers 2024, 16(3), 515; https://doi.org/10.3390/cancers16030515 - 25 Jan 2024
Cited by 1 | Viewed by 1127
Abstract
We aimed to develop a concise objectifiable risk evaluation (CORE) tool for predicting non-relapse mortality (NRM) and overall survival (OS) after allogeneic hematopoietic stem cell transplantation (allo-HCT). A total of 1120 adult patients who had undergone allo-HCT at our center between 2013 and [...] Read more.
We aimed to develop a concise objectifiable risk evaluation (CORE) tool for predicting non-relapse mortality (NRM) and overall survival (OS) after allogeneic hematopoietic stem cell transplantation (allo-HCT). A total of 1120 adult patients who had undergone allo-HCT at our center between 2013 and 2020 were divided into training, first, and second validation cohorts. Objectifiable, patient-related factors impacting NRM in univariate and multivariate analyses were: serum albumin, serum creatinine, serum C-reactive protein (CRP), heart function (LVEF), lung function (VC, FEV1), and patient age. Hazard ratios were assigned points (0–3) based on their impact on NRM and summed to the individual CORE HCT score. The CORE HCT score stratified patients into three distinct low-, intermediate-, and high-risk groups with two-year NRM rates of 9%, 22%, and 46%, respectively, and OS rates of 73%, 55%, and 35%, respectively (p < 0.001). These findings were confirmed in a first and a second recently treated validation cohort. Importantly, the CORE HCT score remained informative across various conditioning intensities, disease-specific subgroups, and donor types, but did not impact relapse incidence. A comparison of CORE HCT vs. HCT Comorbidity Index (HCT-CI) in the second validation cohort revealed better performance of the CORE HCT score with c-statistics for NRM and OS of 0.666 (SE 0.05, p = 0.001) and 0.675 (SE 0.039, p < 0.001) vs. 0.431 (SE 0.057, p = 0.223) and 0.535 (SE 0.042, p = 0.411), respectively. The CORE HCT score is a concise and objectifiable risk evaluation tool for adult patients undergoing allo-HCT for malignant disease. External multicenter validation is underway. Full article
(This article belongs to the Special Issue Blood Stem Cell and Hematological Malignancies)
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Review

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24 pages, 5246 KiB  
Review
Decoding Clonal Hematopoiesis: Emerging Themes and Novel Mechanistic Insights
by Shalmali Pendse and Dirk Loeffler
Cancers 2024, 16(15), 2634; https://doi.org/10.3390/cancers16152634 - 24 Jul 2024
Viewed by 1136
Abstract
Clonal hematopoiesis (CH), the relative expansion of mutant clones, is derived from hematopoietic stem cells (HSCs) with acquired somatic or cytogenetic alterations that improve cellular fitness. Individuals with CH have a higher risk for hematological and non-hematological diseases, such as cardiovascular disease, and [...] Read more.
Clonal hematopoiesis (CH), the relative expansion of mutant clones, is derived from hematopoietic stem cells (HSCs) with acquired somatic or cytogenetic alterations that improve cellular fitness. Individuals with CH have a higher risk for hematological and non-hematological diseases, such as cardiovascular disease, and have an overall higher mortality rate. Originally thought to be restricted to a small fraction of elderly people, recent advances in single-cell sequencing and bioinformatics have revealed that CH with multiple expanded mutant clones is universal in the elderly population. Just a few years ago, phylogenetic reconstruction across the human lifespan and novel sensitive sequencing techniques showed that CH can start earlier in life, decades before it was thought possible. These studies also suggest that environmental factors acting through aberrant inflammation might be a common theme promoting clonal expansion and disease progression. However, numerous aspects of this phenomenon remain to be elucidated and the precise mechanisms, context-specific drivers, and pathways of clonal expansion remain to be established. Here, we review our current understanding of the cellular mechanisms driving CH and specifically focus on how pro-inflammatory factors affect normal and mutant HSC fates to promote clonal selection. Full article
(This article belongs to the Special Issue Blood Stem Cell and Hematological Malignancies)
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