Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study

Myers, Kasiani C.; Furutani, Elissa; Weller, Edie; Siegele, Bradford; Galvin, Ashley; Arsenault, Valérie; Alter, Blanche P.; Boulad, Farid; Bueso‐Ramos, Carlos E.; Burroughs, Lauri M.; Castillo, Paul; Connelly, James; Davies, Stella M.; DiNardo, Courtney D.; Hanif, Iftikhar; Ho, Richard; Karras, Nicole; Manalang, Michelle; McReynolds, Lisa J.; Nakano, Taizo A.; Nalepa, Grzegorz; Norkin, Maxim; Oberley, Matthew J.; Orgel, Etan; Pastore, Yves D.; Rosenthal, Joseph; Walkovich, Kelly; Larson, Jordan; Malsch, Maggie; Elghetany, M. Tarek; Fleming, Mark D.; Shimamura, Akiko

doi:10.1016/s2352-3026(19)30206-6

Cited by 87 publications

(72 citation statements)

References 31 publications

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“…Patients with SDS who develop MDS or AML have poor outcomes, due in part to therapy resistance (42). As would be expected for cells with impaired HR, we found that SBDS-and RPS19-depleted cells had increased sensitivity to PARP inhibition.…”

Section: Discussionsupporting

confidence: 75%

“…SBDS is required for proficient HR repair but not NHEJ. (A) HCT116 (left panel) or U2OS (right panel) cells bearing an integrated DR-GFP HR reporter(42) were transfected with a scrambled (Scr) or one of two SBDS siRNAs (-1 and -2), which targeted unique regions of SBDS RNA. After 48 hours, the cells were co-transfected with an I-Sce1-expressing plasmid to induce a DSB in the DR-GFP reporter and an mCherry-expressing plasmid as a transfection control.…”

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confidence: 99%

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Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

Asik¹,

Chatterjee²,

Bertuch³

2020

Preprint

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Shwachman-Diamond syndrome (SDS) and Diamond-Blackfan anemia (DBA) are ribosomopathies characterized by impaired hematopoiesis and cancer predisposition. The mechanisms underlying cancer predisposition in these disorders are not well understood. We found that LCLs derived from patients with SDS or DBA had a prolonged DNA damage response and hypersensitivity to ionizing radiation, suggesting impaired DNA double strand break (DSB) repair. Consistent with this, depletion of SBDS and RPS19, the most common etiologic factors in SDS and DBA, respectively, resulted in reduced homologous recombination (HR) in HCT116 and U2OS cells. Surprisingly, depletion of EFL1, which functions with SBDS in ribosome biogenesis, did not impair HR and depletion of eIF6, which restores ribosome joining in SBDS-depleted cells, did not rescue the HR defect associated with SBDS depletion. Instead, we found SBDS and RPS19 recruitment to sites of DSBs suggesting that SBDS and RPS19 have more proximate roles in regulating HR, independent of their ribosomal functions. We propose that reduced HR shifts DSB repair toward error-prone NHEJ and this may contribute to oncogenesis in SDS and DBA. Additionally, we found SBDS and RPS19 depleted cells were hypersensitive to PARP inhibition, potentially uncovering a therapeutic target for SDS- and DBA-associated malignancies.

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Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

Asik¹,

Chatterjee²,

Bertuch³

2020

Preprint

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“…The majority of spindle cell/pleomorphic lipomas exhibit 13q14 deletions (mirrored by reduced expression of RB1 protein), 14 chondroid lipomas are characterized by the distinctive C11orf95‐MKL2 gene fusion, 15 lipoblastomas show structural rearrangements involving PLAG1 on chromosome 8q, 16 while hibernomas carry frequent 11q13 rearrangements 17 . Additionally, several types of infiltrating/diffuse proliferations of mature fat are classified under the term lipomatosis, for many of which a genetic basis has been ascertained in the last decade as well 18,19 . In contrast, ALs represent a variant of subcutaneous lipoma that is considered to be endowed with a normal karyotype in most cases, in spite of a recent study on a limited sample of ALs suggesting that structural rearrangements of chromosome 13 might play a role in their pathogenesis 3,20 .…”

Section: Discussionmentioning

confidence: 99%

“…17 Additionally, several types of infiltrating/diffuse proliferations of mature fat are classified under the term lipomatosis, for many of which a genetic basis has been ascertained in the last decade as well. 18,19 In contrast, ALs represent a variant of subcutaneous lipoma that is considered to be endowed with a normal karyotype in most cases, in spite of a recent study on a limited sample of ALs suggesting that structural rearrangements of chromosome 13 might play a role in their pathogenesis. 3,20 In 2017, Hofvander et al detected frequent PRKD2 single nucleotide variants in ALs by means of whole exome sequencing (WES; 80% of cases) 21 ; despite seeming to cluster to the gene portion that encodes the catalytic domain of the protein T A B L E 1 Primer sequences of PIK3CA (exon 9 and exon 20)…”

Section: Mutation Analysismentioning

confidence: 99%

Frequent activating PIK3CA mutations in sporadic angiolipoma

et al. 2020

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BACKGROUND Angiolipoma (AL) is considered as a lipoma variant that is characterized by the combination of mature adipocytes and capillary blood vessels diffusely distributed within the tumor. With the exception of recurrent PRKD2 mutations of uncertain pathogenetic significance, the genetic abnormalities of ALs are unknown, in the absence of any of the specific chromosomal aberrations described in other lipoma variants. METHODS Formalin‐fixed and paraffin‐embedded blocks of 13 conventional ALs and 5 cellular ALs from 17 individuals were retrieved and analyzed for mutations in exons 9 and 20 of PIK3CA by polymerase chain reaction and Sanger sequencing. RESULTS Activating PIK3CA mutations were identified in 14 tumors (78%). All PIK3CA‐mutated samples carried the same exon 9 mutation, c.1634A>C (p.E545A). No mutation was detected in exon 20 of PIK3CA. No significant difference between PIK3CA‐mutated and wild‐type samples appeared to exist based on age, gender, and location of the tumor. All 5 cellular ALs carried the p.E545A PIK3CA mutation. CONCLUSION The high frequency of the p.E545A PIK3CA mutation in both conventional and cellular ALs suggests that activation of the PI3K/AKT pathway plays a key role in AL pathogenesis and reinforces the concept that cellular AL should be regarded as a variant of AL.

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“…Survival of patients with SDS who develop myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) is poor 10 . Therefore, a central goal in clinical care of SDS patients is to identify incipient leukemic transformation and initiate pre-emptive treatment with allogeneic stem cell transplantation.…”

mentioning

confidence: 99%

Distinct genetic pathways define pre-leukemic and compensatory clonal hematopoiesis in Shwachman-Diamond syndrome

Kennedy

Myers

Bowman

et al. 2020

Preprint

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Shwachman-Diamond syndrome (SDS) is an inherited bone marrow failure syndrome with predisposition to developing leukemia. We found that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. EIF6 mutations cause functional compensation for the germline deficiency by alleviating the SDS ribosome joining defect, improving translation, and reducing p53 activation.TP53 mutations decrease checkpoint activation without affecting ribosome assembly. We link development of leukemia with acquisition of biallelic TP53 alterations. Our results define distinct pathways of clonal selection driven by germline fitness constraint and provide a mechanistic framework for clinical surveillance.

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Clinical features and outcomes of patients with Shwachman-Diamond syndrome and myelodysplastic syndrome or acute myeloid leukaemia: a multicentre, retrospective, cohort study

Cited by 87 publications

References 31 publications

Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

Homologous recombination defects in Shwachman-Diamond syndrome and Diamond-Blackfan anemia

Frequent activating PIK3CA mutations in sporadic angiolipoma

Distinct genetic pathways define pre-leukemic and compensatory clonal hematopoiesis in Shwachman-Diamond syndrome

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