Dynamics of clonal evolution in myelodysplastic syndromes

Makishima, Hideki; Yoshizato, Tetsuichi; Yoshida, Kenichi; Sekeres, Mikkael A.; Radivoyevitch, Tomas; Suzuki, Hiromichi; Przychodzen, B.; Nagata, Yasunobu; Meggendorfer, Manja; Sanada, Masashi; Okuno, Yusuke; Hirsch, Cassandra M.; Kuzmanovic, Teodora; Sato, Yusuke; Sato‐Otsubo, Aiko; LaFramboise, Thomas; Hosono, Naoko; Shiraishi, Yuichi; Chiba, Kenichi; Haferlach, Claudia; Kern, Wolfgang; Tanaka, Hiroko; Shiozawa, Yusuke; Gómez-Seguí, Inés; Husseinzadeh, Holleh; Thota, Swapna; Guinta, Kathryn; Dienes, Brittney; Nakamaki, Tsuyoshi; Miyawaki, Shuichi; Saunthararajah, Yogen; Chiba, Shigeru; Miyano, Satoru; Shih, Lee Yung; Haferlach, Torsten; Ogawa, Seishi; Maciejewski, Jaroslaw P.

doi:10.1038/ng.3742

Cited by 342 publications

(379 citation statements)

References 53 publications

Supporting

Mentioning

349

Contrasting

Unclassified

Order By: Relevance

“…A recent large-scale genetic analysis demonstrated that GATA-2 mutations, which were critical for clonal evolution in MDS, had a relatively weaker impact on the progression of AML (Makishima et al 2017). Chromosomal translocations involving GATA-2 upstream enhancer region (−77 kb), such as inv(3)(q21q26) and t(3;3) (q21;q26), contribute to the onset of AML (Gröschel et al 2014;Yamazaki et al 2014).…”

Section: Human Diseases Caused By Gata-2 Dysregulationmentioning

confidence: 99%

GATA Transcription Factors: Basic Principles and Related Human Disorders

Fujiwara

2017

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Section: Human Diseases Caused By Gata-2 Dysregulationmentioning

confidence: 99%

GATA Transcription Factors: Basic Principles and Related Human Disorders

Fujiwara

2017

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

“…Recurrent SF3B1 mutations are therefore likely to play a distinct biological role in MDS-RS pathogenesis. 8 Other studies have identified recurrent SF3B1 mutations in otherwise healthy elderly individuals as evidence that SF3B1 mutations are also involved in premalignant clonal hematopoiesis. 9 In MDS-RS, mitochondrial ferritin accumulates in the mitochondria of the erythroblasts, resulting in accumulation of characteristic ring sideroblasts (RSs), ineffective erythropoiesis, and anemia.…”

Section: Introductionmentioning

confidence: 99%

SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells

Mortera‐Blanco

Dimitriou

Woll

et al. 2017

Blood

View full text Add to dashboard Cite

Key Points• SF3B1 mutations in MDS-RS have a multipotent lymphomyeloid origin.• Transplantation of SF3B1 mutated MDS-RS HSCs into immune-deficient mice results in generation of characteristic ring sideroblasts.Mutations in the RNA splicing gene SF3B1 are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells. While in agreement with previous studies, little or no evidence for clonal (SF3B1 mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for SF3B1 mutations targeting lymphomyeloid HSCs and compatible with mutated SF3B1 negatively affecting lymphoid development. Assessment of stem cell function in vitro as well as in vivo established that only HSCs and not investigated progenitor populations could propagate the SF3B1 mutated clone. Upon transplantation into immune-deficient mice, SF3B1 mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin of SF3B1 mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring SF3B1 mutated MDS-RS. (Blood. 2017;130(7):881-890) Medscape Continuing Medical Education onlineIn support of improving patient care, this activity has been planned and

show abstract

“…For example, mutations in U2AF1 tend to significantly coexist with those in ASXL1, whereas mutations in SF3B1 frequently coexist with those in DNMT3A. [41][42][43] Further efforts to understand the mechanistic and biological contributions of these coexisting mutations on splicing and hematopoiesis may greatly facilitate our understanding of how mutations in RNA splicing promote MDS development.What is the role of RNA splicing factors in MDS development vs maintenance?Mutations in SF3B1, SRSF2, and U2AF1 are consistently expressed in the heterozygous state concomitant with expression of the wild-type allele.1-3 Although the nature of these alterations as heterozygous missense mutations was initially assumed to suggest that they confer a gain of function, it is also now clear that the wild-type allele is absolutely required for cell survival in the setting of expression of the mutant allele 11,23,44 (Figure 2). In contrast, several recent studies have identified that ablation of the mutant RNA splicing factor allele appears to have no effect on cancer maintenance.…”

mentioning

confidence: 99%

“…The lack of requirement for RNA splicing factor mutations in disease maintenance would suggest that these mutations are critically important in disease initiation, a possibility supported by the fact that mutations in RNA splicing factors appear to be some of the earliest genetic events in MDS development. [41][42][43] However, there are currently no studies evaluating this question in genetically defined cells that are not already in a transformed state. These same mutations are also frequently present in clonal hematopoiesis of indeterminate potential, 45,46 a condition highly associated with increased frequency of development of MDS and other myeloid neoplasms.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

How do messenger RNA splicing alterations drive myelodysplasia?

Joshi

Halene

Abdel-Wahab

2017

Blood

View full text Add to dashboard Cite

Mutations in RNA splicing factors are the single most common class of genetic alterations in myelodysplastic syndrome (MDS) patients. Although much has been learned about how these mutations affect splicing at a global-and transcript-specific level, critical questions about the role of these mutations in MDS development and maintenance remain. Here we present the questions to be addressed in order to understand the unique enrichment of these mutations in MDS. (Blood. 2017; 129(18):2465-2470 IntroductionMyelodysplastic syndromes (MDSs) represent clonal disorders of hematopoietic stem cells (HSCs) whereby hematopoietic cell-intrinsic genetic alterations as well as non-cell autonomous factors contribute to an aberrant HSC that produces morphologically abnormal progeny and has impaired ability to generate mature blood cells. Due to the wide clinical and morphologic heterogeneity of MDS, substantial effort has been placed on characterizing the genetic alterations present in MDS cells in hopes of improving our ability to understand, diagnose, and treat the disease. Extensive targeted mutational analysis of protein coding genes has identified that MDS is characterized by a high frequency of mutations in genes encoding messenger RNA (mRNA) splicing factors as well as epigenetic modifiers.1-3 The discovery of mutations in RNA splicing factors in particular was quite unexpected as these mutations are generally uncommon in cancer yet are present in 50% to 60% of MDS patients. Interestingly, there are clear associations between specific mutated splicing factors and subtypes of MDS, most notably mutations in the RNA splicing factor SF3B1 in .90% of patients with MDS with ring sideroblasts.1,2,4 Moreover, the nature of these mutations is quite conspicuous as they occur as heterozygous point mutations at highly recurrent residues. Finally, within MDS patients, these mutations are almost always mutually exclusive; an MDS patient almost never has .1 RNA splicing factor mutation at the same time [1][2][3] (although rare individuals with mutations in .1 RNA splicing factor have been noted, 5 these occur far less frequently than expected by chance in MDS and it is unclear if both mutations in such cases are present within the same cell and/or how the mutations may impact splicing if coexpressed in the same cell).The discovery of RNA splicing factor mutations has led to intense efforts to understand their biological impact on hematopoiesis, 6-9 their genomic and biochemical effects on RNA splicing, 10-21 their structural effects, 22 and potential means to therapeutically target cells bearing these mutations. 8,[23][24][25] Although there have been major advances in understanding the role of RNA splicing factor mutations in MDS pathogenesis and therapy (as reviewed recently [26][27][28] ), major questions about their biological consequences within cells, requirement in disease initiation vs maintenance, and cell autonomous vs nonautonomous roles remain. In addition, numerous questions about the structural and biochemical effects of...

show abstract

Dynamics of clonal evolution in myelodysplastic syndromes

Cited by 342 publications

References 53 publications

GATA Transcription Factors: Basic Principles and Related Human Disorders

GATA Transcription Factors: Basic Principles and Related Human Disorders

SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells

How do messenger RNA splicing alterations drive myelodysplasia?

Contact Info

Product

Resources

About