Haploinsufficient loss of multiple 5q genes may fine-tune Wnt signaling in del(5q) therapy-related myeloid neoplasms

Stoddart, Angela; Nakitandwe, Joy; Chen, Shann-Ching; Downing, James R.; Beau, Michelle M. Le

doi:10.1182/blood-2015-10-673228

Cited by 10 publications

(11 citation statements)

References 11 publications

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“…A strong upregulation of MYC target genes and WNT/β-catenin signaling in EA-Trp53 AML samples ( Fig. 4E and F) modeled our previous expression profiling data of del(5q) t-MN patients, which showed a distinctive upregulation of the MYC oncogene, and deregulated WNT signaling (38,39). In EA-Trp53 samples, compared with EA-Luc MDS, there were a greater number of mice with a clonal chromosomal aberration [75% (6/8) vs. 28% (2/7), P = 0.13], and on average a greater number of aberrations (7 vs. 1.6, P = 0.22; Supplementary Table S2); however, the sample size was small and these differences did not reach statistical significance.…”

Section: Dna Damage Response Genes Are Somatically Mutated In Amls Mosupporting

confidence: 84%

Cytotoxic Therapy–Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms

Stoddart

Wang

Fernald

et al. 2020

Blood Cancer Discovery

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Therapy-related myeloid neoplasms (t-MN) comprise therapy-related acute myeloid leukemia (t-AML) and myelodysplastic syndrome (t-MDS), and are a late complication of cytotoxic therapy, chemotherapy and/or radiotherapy, used in the treatment of both malignant and nonmalignant diseases (1, 2). The genetic profile of t-MN is markedly skewed toward high-risk cytogenetic and molecular abnormalities, and complex karyotypes with deletions of the long arm of chromosome 5, del(5q), and TP53 mutation/loss are profoundly over-represented in t-MNs as compared with de novo counterparts (3, 4). A proximal minimally deleted region (MDR) in 5q31.2 (containing EGR1) was previously identified in t-MN, de novo AML and high-risk MDS, and a distal MDR in 5q33.1(containing mir145, RPS14, and CSNK1A1) was identified in MDS with an isolated del(5q), previously referred to as the 5q-syndrome (1, 5). However, the deletion of 5q in all but rare patients encompasses both MDRs, spanning 5q14-5q33, resulting in loss of one allele for hundreds of genes. Although challenging to identify involved genes, we previously chose to examine two well-characterized del(5q)

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Section: Dna Damage Response Genes Are Somatically Mutated In Amls Mosupporting

confidence: 84%

Cytotoxic Therapy–Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms

Stoddart

Wang

Fernald

et al. 2020

Blood Cancer Discovery

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“…The KG-1 cell line which was established from a patient with erythroleukemia evolving to AML harbored the deletion of 5q11-q31(28). In agreement with our previous finding that Wnt/β-catenin signaling is activated in both del(5q) MDS patients(29) and in t-MDS/t-AML patients with del(5q)(30), expression of β-catenin was significantly higher in MDSL, UoCM1 and KG1 cell lines than it was in Kasumi1, Kasumi3 and MV4-11 human leukemia cells, which do not have chromosome 5 deletion (Fig 3A). Indomethacin, a COX inhibitor, has been reported to inhibit β-catenin expression in vitro and in vivo (31,32).…”

Section: Resultssupporting

confidence: 93%

β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q)

Sheng

et al. 2017

Cancer Research

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Deletion of the chromosome 5q [del(5q)] is one of the most common cytogenetic abnormalities observed in patients with de novo myelodysplastic syndromes (MDS) and therapy-related MDS or acute myeloid leukemia (t-MDS/tAML). Emerging evidence indicates that activation of the Wnt/β-catenin pathway contributes to the development of myeloid neoplasms with del(5q). Whether β-catenin is a potential therapeutic target for myeloid neoplasms with del(5q) has yet to be evaluated. Here we report that genetic deletion of a single allele of β-catenin rescues ineffective hematopoiesis in an Apc haploinsufficient mouse model, which recapitulates several characteristic features of the pre-leukemic stage of myeloid neoplasms with a -5/del(5q). In addition, loss of a single allele of β-catenin reversed the defective self-renewal capacity of Apc-haploinsufficient hematopoietic stem cells (HSC) and reduced the frequency of apoptosis induced by Apc haploinsufficiency. Suppression of β-catenin by indomethacin or β-catenin shRNA reduced proliferation and survival of human leukemia cell lines with del(5q) but not of control leukemia cell lines in vitro; β-catenin inactivation also inhibited leukemia progression in vivo in xenograft mice reconstituted with del(5q) leukemia cell lines. Inhibition of β-catenin also stunted growth and colony-forming abilities of primary bone marrow cells from del(5q) AML patients in vitro. Overall, our data support the idea that β-catenin could serve as a therapeutic target for the treatment of myeloid neoplasms with del(5q).

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“…Haploinsufficient genes implicated in the del(5q) drive distinct disease characteristics, namely anemia ( RPS14 and APC ), megakaryocytic dysplasia ( MIR145 and MIR146A ), HSC expansion ( EGR1 , APC , and CSNK1A1 ), and clonal dominance ( CSNK1A1 ) 53–57 . Including APC , 5q14-q33 contains a total of seventeen genes encoding components and regulators of WNT signaling, a pathway integral to hematopoiesis and leukemogenesis 58 .…”

Section: Somatic Contiguous Gene Syndromesmentioning

confidence: 99%

“…Canonical Wnt signaling plays a role in the regulation of hematopoiesis and the aberrant renewal of leukemia stem cells, and in maintaining the function of the BM niche 123,124 . Gene expression profiling of hematopoietic cells has identified Wnt pathway activation in MDS, AML, and t-MN with a del(5q) 58,125,126 . Deregulation of WNT signaling/CTNNB1 in cancer has been correlated with genomic instability, raising the possibility that this pathway contributes to genomic instability and complex karyotypes characteristic of this subtype of t-MN.…”

Section: Role Of the Bone Marrow Nichementioning

confidence: 99%

Therapy-related myeloid neoplasms: when genetics and environment collide

2017

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Therapy-related myeloid neoplasms (t-MN) arise as a late-effect of chemotherapy and/or radiation administered for a primary condition, typically a malignant disease, solid organ transplant, or autoimmune disease. Survival is measured in months, not years, making t-MN one of the most aggressive and lethal cancers. In this review, we discuss recent developments that reframe our understanding of the genetic and environmental etiology of t-MN. Emerging data illuminate who is at highest risk for developing t-MN, why t-MN is chemoresistant, and how we may use this information to treat and ultimately prevent this dreaded disease.

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Haploinsufficient loss of multiple 5q genes may fine-tune Wnt signaling in del(5q) therapy-related myeloid neoplasms

Cited by 10 publications

References 11 publications

Cytotoxic Therapy–Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms

Cytotoxic Therapy–Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms

β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q)

Therapy-related myeloid neoplasms: when genetics and environment collide

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