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Article
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Hematopoietic stem cells with granulo-monocytic differentiation state overcome venetoclax sensitivity in patients with myelodysplastic syndromes
Secondary resistance to venetoclax in patients with myelodysplastic syndromes (MDS) is not completely elucidated. Here, the authors show that haematopoietic stem cells with a granulo-monocytic differentiation transcriptional state drive secondary resistance to venetoclax in MDS patients who previously failed hypomethylating agent therapy.
- Juan Jose Rodriguez-Sevilla
- , Irene Ganan-Gomez
- & Simona Colla
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Article
| Open Access
Molecular and clinical analyses of PHF6 mutant myeloid neoplasia provide their pathogenesis and therapeutic targeting
PHD finger protein 6 (PHF6) somatic mutations have been identified in blood malignancies. Here, the authors perform genetic analyses of PHF6-mutant myeloid neoplasms which show specific sex-associated genetic correlations and functional collaboration between PHF6 and RUNX1 associated with prognostic value.
- Yasuo Kubota
- , Xiaorong Gu
- & Jaroslaw P. Maciejewski
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Article
| Open Access
BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state
BRD9 is a core non-canonical BAF component. Here the authors show that BRD9 plays a pivotal role in regulating the disease-related cell fate of hematopoietic stem cells. Its loss promotes myeloid skewing while impairing B cell development by altering CTCF-mediated chromatin states.
- Muran Xiao
- , Shinji Kondo
- & Daichi Inoue
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Article
| Open Access
Computational analysis of peripheral blood smears detects disease-associated cytomorphologies
While experts analyze cytomorphology to diagnose myelodysplastic syndromes, definitive diagnosis requires complementary information such as karyotype and molecular genetics testing. Here, the authors present a computational method that automatically detects, characterizes and helps identify blood cell characteristics associated with this group of diseases.
- José Guilherme de Almeida
- , Emma Gudgin
- & Moritz Gerstung
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Article
| Open Access
Molecular patterns identify distinct subclasses of myeloid neoplasia
Myeloid neoplasias can show complex mutation patterns and molecular features. Here, the authors apply machine learning to classify risk groups of myeloid neoplasia which may correlate with differential response to treatment.
- Tariq Kewan
- , Arda Durmaz
- & Jaroslaw P. Maciejewski
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Article
| Open Access
Inhibition of lysyl oxidases synergizes with 5-azacytidine to restore erythropoiesis in myelodysplastic and myeloid malignancies
Hypomethylating agents, such as 5-Azacytidine (5-AZA), are standard of care for patients with myelodysplastic and myeloid malignancies, however response rates are limited and risk of relapses high. Here the authors show that inhibition of lysyl oxidases synergizes with 5-AZA to improve erythropoiesis and reduce disease burden in myelodysplastic neoplasms models.
- Qingyu Xu
- , Alexander Streuer
- & Daniel Nowak
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Article
| Open Access
Myelodysplastic Syndrome associated TET2 mutations affect NK cell function and genome methylation
Myelodysplastic syndromes are characterised by clonal haematopoiesis, with the affected cells often harbouring mutations in the TET2 gene, an important regulator of DNA methylation state. Here authors show that the same mutations are also found in NK cells, perturbing their DNA methylation pattern and cytolytic function.
- Maxime Boy
- , Valeria Bisio
- & Nicolas Dulphy
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Article
| Open Access
The transcription factor DDIT3 is a potential driver of dyserythropoiesis in myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are age-related pathologies in which alterations of hematopoietic stem cells lead to abnormal formation of blood cells. Here, the authors study the lesions that these cells undergo in aging and disease, characterizing a factor whose alteration in MDS leads to abnormal blood cell production.
- Nerea Berastegui
- , Marina Ainciburu
- & Felipe Prosper
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Article
| Open Access
Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia
‘Mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with poor clinical outcome, however, their impact on chromatin dynamics remains unexplored. Here the authors use a multi-omics approach for chronic myelomonocytic leukemia (CMML) and investigate the transcriptome and chromatin landscape of ASXL1MT CMML.
- Moritz Binder
- , Ryan M. Carr
- & Mrinal M. Patnaik
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Article
| Open Access
Bone marrow sinusoidal endothelium controls terminal erythroid differentiation and reticulocyte maturation
Niche crosstalk with Haematopoietic cells underlies normal haematopoiesis and myeloid disorders. Here the authors report a Stabilin2-Cre driver mouse with Cre-activity restricted to bone marrow sinusoidal endothelial cells, and that Stabilin2-Cre driven overactivation of b-catenin leads to erythroid differentiation defects and anaemia.
- Joschka Heil
- , Victor Olsavszky
- & Philipp-Sebastian Koch
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Article
| Open Access
Bone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo
Bone marrow-derived mesenchymal stroma cells (MSCs) in myeloid neoplasia have been hypothesized to carry somatic mutations and contribute to pathogenesis. Here the authors analyse ex-vivo cultures and primary MSCs derived from patients with myelodysplastic syndromes, finding functional alterations but no evidence of clonal mutations.
- Johann-Christoph Jann
- , Maximilian Mossner
- & Daniel Nowak
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Article
| Open Access
Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis
Azacitidine (AZA) treatment is used for patients with myelodysplasias that cannot undergo bone marrow transplantation; however, AZA treatment is only partially effective. Here the authors show synergy of AZA with compounds inhibiting the chromatin regulators CBP and p300, which is mediated by the RNA-dependent functions of AZA affecting protein translation.
- Jeannine Diesch
- , Marguerite-Marie Le Pannérer
- & Marcus Buschbeck
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| Open Access
RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis
Chronic myelomonocytic leukaemia is classified as proliferative (pCMML) or dysplastic based on the white blood cell counts but biological differences are unclear. Here, the authors show genetic, transcriptomic and epigenomic differences between these two subtypes establishing that pCMML is RAS-pathway driven and that inhibiting RAS-driven PLK1 expression is a viable therapeutic target.
- Ryan M. Carr
- , Denis Vorobyev
- & Mrinal M. Patnaik
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Article
| Open Access
Cut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia
Cut-like homeobox 1 (CUX1) is a haploinsufficient tumor suppressor commonly inactivated in acute myeloid leukemia and high-risk myelodysplasia. Here, in a genetically modified murine model, the authors show that CUX1 deficiency impairs apoptosis leading to leukemia when combined with mutant Flt3-ITD.
- Emmanuelle Supper
- , Saskia Rudat
- & Chi C. Wong
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Article
| Open Access
Mutant ASXL1 induces age-related expansion of phenotypic hematopoietic stem cells through activation of Akt/mTOR pathway
ASXL1 mutations are frequently found in age-related clonal haemaotopoiesis (CH), but how they drive CH is unclear. Here the authors show that expression of C-terminal truncated ASXL1 in haematopoietic stem cells (HSCs) leads to Akt de-ubiquitination, activated Akt/mTOR signaling, and aberrant HSC proliferation.
- Takeshi Fujino
- , Susumu Goyama
- & Toshio Kitamura
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Article
| Open Access
The acquisition of molecular drivers in pediatric therapy-related myeloid neoplasms
Paediatric therapy-related myeloid neoplasms (tMN) have a dismal prognosis and have not been comprehensively profiled. Here the authors characterise the molecular landscape of 84 paediatric tMN patients, and find that, unlike adult tMNs, these do not emerge from pre-existing clones and that MECOM dysregulation is frequent.
- Jason R. Schwartz
- , Jing Ma
- & Jeffery M. Klco
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| Open Access
Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia
The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells in the majority of patients with leukemia but not during normal blood formation. Here, the authors report a mouse model with conditional Cdx2 expression showing de novo leukemic transformation, and use it to optimize treatment in high-risk AML.
- Therese Vu
- , Jasmin Straube
- & Steven W. Lane
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| Open Access
Invariant patterns of clonal succession determine specific clinical features of myelodysplastic syndromes
Stepwise acquisition of mutations gives rise to myelodysplastic syndrome (MDS) in older adults. Here, the authors infer the clonal hierarchy of 1809 MDS patients, revealing insights into the evolution of dominant/secondary mutations and how these impact clinical phenotypes like leukemic progression and therapy response.
- Yasunobu Nagata
- , Hideki Makishima
- & Jaroslaw P. Maciejewski
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Article
| Open Access
A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies
Myelodyplastic hematopoietic stem cells (MDS HSC) have eluded in vivo modeling. Here the authors present a highly efficient MDS patient-derived xenotransplantation model in cytokine-humanized mice with replication of the donors’ genetic complexity and myeloid, erythroid, and megakaryocytic lineage dysplasia.
- Yuanbin Song
- , Anthony Rongvaux
- & Stephanie Halene
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Article
| Open Access
A miR-150/TET3 pathway regulates the generation of mouse and human non-classical monocyte subset
A decrease in the fraction of non-classical monocytes is a hallmark of chronic myelomonocytic leukaemia. Taking advantage of this abnormal situation, the authors identify a mechanistic link between miR-150 and TET3 as being involved in monocyte subset generation.
- Dorothée Selimoglu-Buet
- , Julie Rivière
- & Eric Solary
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Article
| Open Access
Aberrant splicing and defective mRNA production induced by somatic spliceosome mutations in myelodysplasia
Mutations to the splicing machinery may have an important role in myelodysplasia. Here, the authors describe splicing factor gene mutations in myelodysplasia and report tumor suppressor, epigenetic, iron metabolism and heme biosynthesis genes as their targets.
- Yusuke Shiozawa
- , Luca Malcovati
- & Mario Cazzola
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Article
| Open Access
miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFβ signaling
Myelodysplastic syndrome (MDS) is characterized by altered hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) regulation and reduction of miR-143 and miR-145 in some subtypes. Here the authors show that miR-143/145 loss leads to HSC depletion, HPC expansion and malignancy through Dab2 -mediated TGFβ pathway activation.
- Jeffrey Lam
- , Marion van den Bosch
- & Aly Karsan
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Article
| Open Access
Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential
Cellular stressors can impact clonal hematopoiesis. Here, the authors explore the impact of cytotoxic therapy and hematopoietic transplantation on clonal expansion, suggesting different stressors can promote expansion of distinct long-lived clones.
- Terrence N. Wong
- , Christopher A. Miller
- & Daniel C. Link
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Article
| Open Access
The genomic landscape of pediatric myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are uncommon in children and have poor prognosis. Here, the authors interrogate the genomic landscape of MDS, confirming adult and paediatric MDS are separate diseases with disparate mechanisms, and highlighting that SAMD9/SAMD9L mutations represent a new class of MDS predisposition.
- Jason R. Schwartz
- , Jing Ma
- & Jeffery M. Klco
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Article
| Open Access
Loss of Asxl2 leads to myeloid malignancies in mice
ASXL2 mutations are mostly found in a subset of leukemia patients with certain genetic aberrations; however the role of this protein in normal hematopoiesis and related malignancies is still unclear. Here the authors use a knock-out mouse model to uncover the role of Asxl2in hematopoiesis and leukemogenesis.
- Jianping Li
- , Fuhong He
- & Feng-Chun Yang
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Article
| Open Access
Clonal evolution in myelodysplastic syndromes
Myelodysplastic syndromes are a broad group of haematopoietic malignancies that often progress to acute myeloid leukaemia. Here, the authors show that linear and branched evolution occurs within myelodysplastic syndrome and these patterns can be impacted by treatment.
- Pedro da Silva-Coelho
- , Leonie I. Kroeze
- & Joop H. Jansen
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Article
| Open Access
Mutant U2AF1-expressing cells are sensitive to pharmacological modulation of the spliceosome
Spliceosome mutations occur in approximately 50% of patients with myelodysplastic syndromes. Here, the authors show that tumour cells harbouring theS34F mutation in the U2AFspliceosome gene is sensitive to compounds that further perturb the spliceosome.
- Cara Lunn Shirai
- , Brian S. White
- & Matthew J. Walter
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Article
| Open Access
MSI2 is required for maintaining activated myelodysplastic syndrome stem cells
Several studies have recently demonstrated the role of the MSI2 RNA binding protein in normal and malignant haematopoietc stem cells. In this study, the authors show that MSI2 is required for maintaining myelodysplastic syndrome stem cells in mice and that MSI2 expression predicts poor prognosis in patients affected by this disease.
- James Taggart
- , Tzu-Chieh Ho
- & Michael G. Kharas
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Article
| Open Access
SF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with diverse phenotypes and can derive from hematopietic stem cells after the acquisition of specific somatic aberrations. In this study, the authors show that MDS initiating cells in some cases of sideroblastic anemia with SF3B1 mutations, can arise from hematopoietic stem cells.
- Syed A. Mian
- , Kevin Rouault-Pierre
- & Ghulam J. Mufti
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Article
| Open Access
Whole-exome and targeted sequencing identify ROBO1 and ROBO2 mutations as progression-related drivers in myelodysplastic syndromes
The molecular events that drive the disease progression of myelodysplastic syndromes are poorly understood. Here, the authors report the identification of novel progression-related somatic mutations in ROBO1 and ROBO2, highlighting ROBO-SLIT2 signalling in the pathogenesis of MDS.
- Feng Xu
- , Ling-Yun Wu
- & Xiao Li
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Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome
Somatic mutations in components of the core RNA splicing machinery, including ZRSR2, have been implicated in myelodysplastic syndrome (MDS). Here, Madan et al.show that ZRSR2 plays a pivotal role in splicing of the U12-type introns, while the U2-dependent splicing is largely unaffected in ZRSR2 mutant MDS bone marrow.
- Vikas Madan
- , Deepika Kanojia
- & H. Phillip Koeffler
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Article
| Open Access
Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes
The myelodysplastic syndromes (MDS) are a heterogeneous group of chronic blood cancers. Here, the authors analyse genomic and gene expression data from MDS patients to investigate how driver mutations alter gene expression, diagnostic clinical variables and survival.
- Moritz Gerstung
- , Andrea Pellagatti
- & Jacqueline Boultwood
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Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukaemic transformation
Mutations in the EZH2 gene are found in myelodysplastic syndrome (MDS) and are often accompanied by mutations in RUNX1. Here, the authors develop a mouse model of MDS and show that EZH2loss enhances the RUNX1-mediated MDS pathology.
- Goro Sashida
- , Hironori Harada
- & Atsushi Iwama
Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation