Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

Download Full-text

Monosomy 7 As the Initial Hit Followed By Sequential Acquisition of SETBP1 and ASXL1 Driver Mutations in Childhood Myelodysplastic Syndromes

Blood ◽

10.1182/blood-2018-99-118910 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 105-105 ◽

Cited By ~ 1

Author(s):

Victor Pastor Loyola ◽

Pritam Kumar Panda ◽

Sushree Sangita Sahoo ◽

Enikoe Amina Szvetnik ◽

Emilia J. Kozyra ◽

...

Keyword(s):

Deep Sequencing ◽

Myelodysplastic Syndromes ◽

Somatic Mutations ◽

Clonal Evolution ◽

Driver Mutations ◽

Common Denominator ◽

Hematopoietic Stem ◽

Monosomy 7 ◽

Clonal Architecture ◽

Over Time

Abstract Childhood myelodysplastic syndromes (MDS) account for less than 5% of pediatric hematologic malignancies and differ from their adult counterpart in terms of biology, genetics, and cure rates. Complete (-7) or partial loss (del7q) of chromosome 7 constitutes the most common cytogenetic abnormality and is associated with more advanced disease typically requiring timely hematopoietic stem cell transplantation (HSCT). Previously, we and others established a link between -7 and germline GATA2 mutations in pediatric MDS (37% of MDS/-7 cases are GATA2-deficient) as well as constitutional SAMD9/9L disorders where -7 is utilized as an escape mechanism from the growth-restrictive effect of SAMD9/9L mutations. To date, comprehensive sequencing studies have been performed in 96 children with primary MDS, as reported by Pastor et al, Leukemia 2017 and Schwartz et al, Nature Comm 2017. This work established mutations in SETBP1, ASXL1, PTPN11, RUNX1 and RAS pathway genes as common somatic drivers. However, little is known about the clonal development of -7 and the role of additional somatic mutations. The knowledge about clonal hierarchies is essential for the understanding of disease progression on molecular level and for mapping potential drug targets. The rationale for the current study was to i) define the most common somatic drivers in a large cohort of patients with childhood MDS, ii) identify clonal/subclonal mutations, iii) infer clonal architecture of monosomy 7 and track the changes over time. We studied a cohort of 576 children and adolescents with primary MDS diagnosed between 1998 and 2016 in Germany, consisting of 482 (83%) patients with refractory cytopenia of childhood (RCC) and 94 (17%) MDS with excess blasts (EB). All patients underwent deep sequencing for 30 genes relevant to pediatric MDS and additional WES was performed in 150/576 patients. Using 20 computational predictors (including CADD and REVEL), population databases and germline testing, we identified the most likely pathogenic mutations. First, we excluded germline predisposing mutations in GATA2, SAMD9/SAMD9L and RUNX1 detected in 7% (38/576), 8% (43 of 548 evaluable) and 0.7% (4/576) of patients, respectively. Then we focused on the exploration of somatic aberrations. Most common karyotype abnormalities were monosomy 7 (13%, 77/576) and trisomy 8 (3%, 17/576). A total of 104 patients carried somatic mutations, expectedly more prevalent in the MDS-EB group as compared to RCC (56%, 53/94 vs 10.6%, 51/482; p<0.0001). The most recurrent somatic hits (≥ 1% frequency within 576 cases) were in SETBP1 (4.2%), ASXL1 (3.8%), RUNX1 (3.3%), NRAS (2.9%), KRAS (1.6%), PTPN11 (1.4%) and STAG2 (1%). We next focused on the -7 karyotype as a common denominator for the mutated group. Mutations were found in 54% (43/79), and the mutational load was significantly higher in -7 vs. non-7 (1.1 vs. 0.1 mutations per patient; p<0.001). In 11 patients with -7 and concomitant SETBP1/ASXL1 driver mutations, SETBP1 surpassed ASXL1 hits (median allelic frequency: 38% vs. 24%, p<0.05), while mutations in other genes were subclonal. Notably, these clonal patterns were independent of the underlying hereditary predisposition (4/11 GATA2; 3/11 SAMD9L). To explore the clonal hierarchy in MDS/-7 we performed targeted sequencing of several hundreds of single bone marrow derived colony forming cells (CFC) in 7 patients with MDS/-7. In all cases, the -7 clone was the founding clone followed by stepwise acquisition of mutations (i.e. -7>SETBP1>ASXL1; -7>SETBP1>ASXL1>PTPN11; -7>SETBP1>ASXL1>CBL, -7>EZH2>PTPN11). Finally, we tracked clonal evolution over time in 12 cases with 2-12 available serial samples using deep sequencing complemented by serial CFC-analysis. This confirmed that SETBP1 clones are rapidly expanding, while ASXL1 subclones exhibit an unstable pattern with clonal sweeping, while additional minor clones are acquired as late events. In 2 of 11 transplanted patients who experienced relapse, the original clonal architecture reappeared after HSCT. In summary, the hierarchy of clonal evolution in pediatric MDS with -7 follows a defined pattern with -7 aberrations arising as ancestral event followed by the acquisition of somatic hits. SETBP1 mutations are the dominant driver while co-dominant ASXL1 mutations are unstable. The functional interdependence and potential pharmacologic targetability of such somatic lesions warrants further studies. Disclosures Niemeyer: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Genes ◽

10.3390/genes12081144 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1144

Author(s):

Chiara Chiereghin ◽

Erica Travaglino ◽

Matteo Zampini ◽

Elena Saba ◽

Claudia Saitta ◽

...

Keyword(s):

Disease Progression ◽

Myelodysplastic Syndromes ◽

Clinical Relevance ◽

Driver Mutations ◽

Significant Information ◽

Hematopoietic Stem ◽

Probability Of Survival ◽

Mutational Status ◽

Increased Risk ◽

Risk Of Disease

Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in <5% of cases. At diagnosis, the majority of MDS patients have 2–4 driver mutations and hundreds of background mutations. Reliable genotype/phenotype relationships were described in MDS: SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance.

Download Full-text

Pathophysiology of Myelodysplastic Syndromes

Hemato ◽

10.3390/hemato2030030 ◽

2021 ◽

Vol 2 (3) ◽

pp. 477-495

Author(s):

Michaela Fontenay ◽

Batoul Farhat ◽

Ismael Boussaid

Keyword(s):

Myelodysplastic Syndromes ◽

Tumor Response ◽

Clonal Evolution ◽

Epistatic Interactions ◽

Hematopoietic Stem ◽

Effector Cells ◽

Inflammatory State ◽

Immune Contexture ◽

Immunosuppressive Cells ◽

Genetic Events

Ineffective hematopoiesis is the major characteristic of early myelodysplastic syndromes. Its pathophysiology relies on a diversity of mechanisms supported by genetic events that develop in aging hematopoietic stem cells. Deletion and mutations trigger epigenetic modifications, and co-transcriptional and post-transcriptional deregulations of gene expression. Epistatic interactions between mutants may aggravate the phenotype. Amplification of minor subclones containing mutations that promote their growth and suppress the others drives the clonal evolution. Aging also participates in reprogramming the immune microenvironment towards an inflammatory state, which precedes the expansion of immunosuppressive cells such as Tregs and myeloid-derived suppressive cells that alters the anti-tumor response of effector cells. Integrating biomarkers of transcription/translation deregulation and immune contexture will help the design of personalized treatments.

Download Full-text

Secondary CNL after SAA reveals insights in leukemic transformation of bone marrow failure syndromes

Blood Advances ◽

10.1182/bloodadvances.2020001541 ◽

2020 ◽

Vol 4 (21) ◽

pp. 5540-5546

Author(s):

Laurent Schmied ◽

Patricia A. Olofsen ◽

Pontus Lundberg ◽

Alexandar Tzankov ◽

Martina Kleber ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Myeloid Leukemia ◽

Bone Marrow Failure ◽

Driver Mutations ◽

Leukemic Transformation ◽

Hematopoietic Stem ◽

Bone Marrow Failure Syndromes ◽

Proinflammatory Responses ◽

Stem And Progenitor Cells

Abstract Acquired aplastic anemia and severe congenital neutropenia (SCN) are bone marrow (BM) failure syndromes of different origin, however, they share a common risk for secondary leukemic transformation. Here, we present a patient with severe aplastic anemia (SAA) evolving to secondary chronic neutrophilic leukemia (CNL; SAA-CNL). We show that SAA-CNL shares multiple somatic driver mutations in CSF3R, RUNX1, and EZH2/SUZ12 with cases of SCN that transformed to myelodysplastic syndrome or acute myeloid leukemia (AML). This molecular connection between SAA-CNL and SCN progressing to AML (SCN-AML) prompted us to perform a comparative transcriptome analysis on nonleukemic CD34high hematopoietic stem and progenitor cells, which showed transcriptional profiles that resemble indicative of interferon-driven proinflammatory responses. These findings provide further insights in the mechanisms underlying leukemic transformation in BM failure syndromes.

Download Full-text

Inflammation as a Driver of Clonal Evolution in Myeloproliferative Neoplasm

Mediators of Inflammation ◽

10.1155/2015/606819 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 12

Author(s):

Angela G. Fleischman

Keyword(s):

Inflammatory Response ◽

Characteristic Feature ◽

Progenitor Cells ◽

Clonal Evolution ◽

Myeloproliferative Neoplasm ◽

Clonal Expansion ◽

Selective Advantage ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells ◽

The Impact

Our understanding of inflammation’s role in the pathogenesis of myeloproliferative neoplasm (MPN) is evolving. The impact of chronic inflammation, a characteristic feature of MPN, likely goes far beyond its role as a driver of constitutional symptoms. An inflammatory response to the neoplastic clone may be responsible for some pathologic aspects of MPN. Moreover,JAK2V617Fmutated hematopoietic stem and progenitor cells are resistant to inflammation, and this gives the neoplastic clone a selective advantage allowing for its clonal expansion. Because inflammation plays a central role in MPN inflammation is a logical therapeutic target in MPN.

Download Full-text

Bone marrow oxidative stress and specific antioxidant signatures in myelodysplastic syndromes

Blood Advances ◽

10.1182/bloodadvances.2019000677 ◽

2019 ◽

Vol 3 (24) ◽

pp. 4271-4279 ◽

Cited By ~ 8

Author(s):

Frederic Picou ◽

Christine Vignon ◽

Christelle Debeissat ◽

Sébastien Lachot ◽

Olivier Kosmider ◽

...

Keyword(s):

Bone Marrow ◽

Progenitor Cells ◽

Myelodysplastic Syndromes ◽

Disulfide Bonds ◽

Cellular Response ◽

Antioxidant Response ◽

Disease Diagnosis ◽

Redox Metabolism ◽

Secondary Acute Myeloid Leukemia ◽

Stem And Progenitor Cells

Abstract Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for transformation in secondary acute myeloid leukemia. This study focused on the redox metabolism of bone marrow (BM) cells from 97 patients compared with 25 healthy controls. The level of reactive oxygen species (ROS) was quantified by flow cytometry in BM cell subsets as well as the expression level of 28 transcripts encoding for major enzymes involved in the antioxidant cellular response. Our results highlight increased ROS levels in BM nonlymphoid cells and especially in primitive CD34posCD38low progenitor cells. Moreover, we identified a specific antioxidant signature, dubbed “antioxidogram,” for the different MDS subgroups or secondary acute myeloblastic leukemia (sAML). Our results suggest that progression from MDS toward sAML could be characterized by 3 successive molecular steps: (1) overexpression of enzymes reducing proteic disulfide bonds (MDS with <5% BM blasts [GLRX family]); (2) increased expression of enzymes detoxifying H2O2 (MDS with 5% to 19% BM blasts [PRDX and GPX families]); and finally (3) decreased expression of these enzymes in sAML. The antioxidant score (AO-Score) defined by logistic regression from the expression levels of transcripts made it possible to stage disease progression and, interestingly, this AO-Score was independent of the revised International Scoring System. Altogether, this study demonstrates that MDS and sAML present an important disturbance of redox metabolism, especially in BM stem and progenitor cells and that the specific molecular antioxidant response parameters (antioxidogram, AO-Score) could be considered as useful biomarkers for disease diagnosis and follow-up.

Download Full-text

Analysis of Mesenchymal Stromal Cells (MSC) and Their Interactions with CD34 Stem and Progenitor Cells in Patients with Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v118.21.2393.2393 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2393-2393

Author(s):

Stefanie Geyh ◽

Ron Patrick Cadeddu ◽

Julia Fröbel ◽

Ingmar Bruns ◽

Fabian Zohren ◽

...

Keyword(s):

Progenitor Cells ◽

Myelodysplastic Syndromes ◽

Stromal Cells ◽

Median Number ◽

Lower Number ◽

Differentiation Potential ◽

Receptor Ligand ◽

Hematopoietic Stem ◽

Cd34 Cells ◽

Stem And Progenitor Cells

Abstract Abstract 2393 Background: Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematopoietic stem cell disorders and research in this field has mainly focused on hematopoietic stem and progenitor cells (HSPC). Still, recent data from mouse models indicate that the bone marrow (BM) microenvironment might be involved in the pathogenesis MDS (Raaijmakers et al., 2010). The role of mesenchymal stromal cells (MSC) in particular as a key component of the BM microenvironment remains elusive in human MDS and data so far are controversial. Design/Methods: We therefore investigated MSC and immunomagnetically enriched CD34+ HSPC from BM of 42 untreated patients (pts) with MDS (12 RCMD, 12 RAEB, 12 sAML, 3 del5q, 1 CMML-1, 1 MDS hypocellular, 1 MDS unclassifiable according to WHO) and age-matched healthy controls (HC, n=13). MSC were examined with regard to growth kinetics, morphology and differential potential after isolation and expansion according standard procedures in line with the international consensus criteria (Dominici et al., 2006). Furthermore corresponding receptor-ligand pairs on MSC and CD34+ cells (Kitlg/c-kit; CXCL12/CXCR4; Jagged1/Notch1; Angpt1-1/Tie-2; ICAM1/LFA-1) were investigated by RT-PCR. Results: In MDS, the colony forming activity (CFU-F) of MSC was significantly reduced in comparison to HC (median number of colonies per 1×107MNC in MDS: 8, range 2–74 vs. HC: 175, 10–646, p=0.003) and this was also true when looking at the different subtypes (RCMD median: 16, p=0.04; RAEB median: 8, p=0.31; sAML median: 26, p=0.02). According to this, MSC from pts with RCMD and del5q could only be maintained in culture for a lower number of passages (median number of passages: MDS 3 passages, range 1–15; HD 14 passages, range 8–15, p=0.01), had a lower number of cumulative population doublings (CPD) and needed a longer timer to reach equivalent CPD (MDS median: 18,16 CPD, HD median: 33,68 CPD, p=0,0059). All types of MDS-MSC showed an abnormal morphology, while an impaired osteogenic differentiation potential was exclusively observed in pts with RCMD. These findings of an altered morphology together with a diminished growth and differentiation potential prompted us to test, whether the interaction between MSC and CD34+ HSPC in BM of pts with MDS was also disturbed. On the MDS-MSC, we found a significant lower expression of Angpt1 in pts with RAEB (3.5-fold, p=0.01) and del5q (4.9-fold, p=0.009) compared to HD. The expression of CXCL12 (2.5-fold, p=0.057) and jagged1 was reduced in trend in MSC from pts with MDS, while no differences were observed with regard to the expression of kitlg and ICAM1. When looking on CD34+ cells, we found a significantly reduced expression of CXCR4 (RCMD 2.5-fold, p=0.02; RAEB 2.46-fold, p=0.02), notch1 (RCMD 6-fold, p=0.04) and Tie-2 (RAEB 5.91-fold, p=0.02) in pts with MDS, while LFA-1 was overexpressed in pts with RAEB (2.6-fold, p=0.036). Conclusion: Taken together, our data indicate that MSC from pts with MDS are structurally altered and that the crosstalk between CD34+ HSPC and MSC in the BM microenvironment of pts with MDS might be deregulated as a result of an abnormal expression of relevant receptor-ligand pairs. Ongoing research is required to corroborate these findings and to definitely address their functional relevance for the pathogenesis of MDS. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Clonal hematopoiesis is associated with risk of severe Covid-19

Nature Communications ◽

10.1038/s41467-021-26138-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kelly L. Bolton ◽

Youngil Koh ◽

Michael B. Foote ◽

Hogune Im ◽

Justin Jee ◽

...

Keyword(s):

Driver Mutations ◽

Tumor Patients ◽

Hematopoietic Stem ◽

Cancer Driver ◽

Clonal Hematopoiesis ◽

Increased Risk ◽

Stem And Progenitor Cells ◽

Severe Infections ◽

The Relationship ◽

Immunologic Profile

AbstractAcquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10−3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

Download Full-text

Aging- and Senescence-associated Changes of Mesenchymal Stromal Cells in Myelodysplastic Syndromes

Cell Transplantation ◽

10.1177/0963689717745890 ◽

2018 ◽

Vol 27 (5) ◽

pp. 754-764 ◽

Cited By ~ 9

Author(s):

Domenico Mattiucci ◽

Giulia Maurizi ◽

Pietro Leoni ◽

Antonella Poloni

Keyword(s):

Progenitor Cells ◽

Mesenchymal Stromal Cells ◽

Myelodysplastic Syndromes ◽

Stromal Cells ◽

Replicative Senescence ◽

Special Focus ◽

Proliferative Potential ◽

Stromal Compartment ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells

Hematopoietic stem and progenitor cells reside within the bone marrow (BM) microenvironment. By a well-balanced interplay between self-renewal and differentiation, they ensure a lifelong supply of mature blood cells. Physiologically, multiple different cell types contribute to the regulation of stem and progenitor cells in the BM microenvironment by cell-extrinsic and cell-intrinsic mechanisms. During the last decades, mesenchymal stromal cells (MSCs) have been identified as one of the main cellular components of the BM microenvironment holding an indispensable role for normal hematopoiesis. During aging, MSCs diminish their functional and regenerative capacities and in some cases encounter replicative senescence, promoting inflammation and cancer progression. It is now evident that alterations in specific stromal cells that comprise the BM microenvironment can contribute to hematologic malignancies, and there is growing interest regarding the contribution of MSCs to the pathogenesis of myelodysplastic syndromes (MDSs), a clonal hematological disorder, occurring mostly in the elderly, characterized by ineffective hematopoiesis and increased tendency to acute myeloid leukemia evolution. The pathogenesis of MDS has been associated with specific genetic and epigenetic events occurring both in hematopoietic stem cells (HSCs) and in the whole BM microenvironment with an aberrant cross talk between hematopoietic elements and stromal compartment. This review highlights the role of MSCs in MDS showing functional and molecular alterations such as altered cell-cycle regulation with impaired proliferative potential, dysregulated cytokine secretion, and an abnormal gene expression profile. Here, the current knowledge of impaired functional properties of both aged MSCs and MSCs in MDS have been described with a special focus on inflammation and senescence induced changes in the BM microenvironment. Furthermore, a better understanding of aberrant BM microenvironment could improve future potential therapies.

Download Full-text

Stem Cells in the Myelodysplastic Syndromes

Frontiers in Aging ◽

10.3389/fragi.2021.719010 ◽

2021 ◽

Vol 2 ◽

Author(s):

Di Zhan ◽

Christopher Y. Park

Keyword(s):

Stem Cells ◽

Myelodysplastic Syndromes ◽

Molecular Mechanisms ◽

Clonal Evolution ◽

Surface Proteins ◽

Epigenetic Alterations ◽

Hematopoietic Stem ◽

Innate Immune Signaling ◽

Novel Therapeutic Strategies

The myelodysplastic syndromes (MDS) represent a group of clonal disorders characterized by ineffective hematopoiesis, resulting in peripheral cytopenias and frequent transformation to acute myeloid leukemia (AML). We and others have demonstrated that MDS arises in, and is propagated by malignant stem cells (MDS-SCs), that arise due to the sequential acquisition of genetic and epigenetic alterations in normal hematopoietic stem cells (HSCs). This review focuses on recent advancements in the cellular and molecular characterization of MDS-SCs, as well as their role in mediating MDS clinical outcomes. In addition to discussing the cell surface proteins aberrantly upregulated on MDS-SCs that have allowed the identification and prospective isolation of MDS-SCs, we will discuss the recurrent cytogenetic abnormalities and genetic mutations present in MDS-SCs and their roles in initiating disease, including recent studies demonstrating patterns of clonal evolution and disease progression from pre-malignant HSCs to MDS-SCs. We also will discuss the pathways that have been described as drivers or promoters of disease, including hyperactivated innate immune signaling, and how the identification of these alterations in MDS-SC have led to investigations of novel therapeutic strategies to treat MDS. It is important to note that despite our increasing understanding of the pathogenesis of MDS, the molecular mechanisms that drive responses to therapy remain poorly understood, especially the mechanisms that underlie and distinguish hematologic improvement from reductions in blast burden. Ultimately, such distinctions will be required in order to determine the shared and/or unique molecular mechanisms that drive ineffective hematopoiesis, MDS-SC maintenance, and leukemic transformation.

Download Full-text