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. 2018 Nov 22;132(21):2309-2313.
doi: 10.1182/blood-2017-05-787390. Epub 2018 Oct 15.

Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes

Yasunobu Nagata  1 , Satoshi Narumi  2 , Yihong Guan  1 , Bartlomiej P Przychodzen  1 , Cassandra M Hirsch  1 , Hideki Makishima  3 , Hirohito Shima  2 , Mai Aly  1   4 , Victor Pastor  5 , Teodora Kuzmanovic  1 , Tomas Radivoyevitch  1   6 , Vera Adema  1 , Hassan Awada  1 , Kenichi Yoshida  3 , Samuel Li  7 , Francesc Sole  8 , Rabi Hanna  9 , Babal K Jha  1 , Thomas LaFramboise  7 , Seishi Ogawa  3 , Mikkael A Sekeres  10 , Marcin W Wlodarski  5 , Jörg Cammenga  11 , Jaroslaw P Maciejewski  1
Affiliations

Germline loss-of-function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes

Yasunobu Nagata et al. Blood. .
No abstract available

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Characteristic of GL SAMD9/SAMD9L variants in adult MDS. (A) Positions and types of GL SAMD9 and SAMD9L variants detected in adult patients with MDS and BMF (above the 2 genes). Reported SAMD9 and SAMD9L variants in familial pediatric MDS and BMFs are also depicted (below the 2 genes). Functional sterile α motif (SAM) is shown in green. (B) Frequencies of specific SAMD9 and SAMD9L GL variants in our cohort and ethnically matched healthy controls. Distribution of GL SAMD9 (C) and SAMD9L (D) variants between adult and pediatric MDS. Three genetic regions (N terminus, enter, and C terminus) were defined with equal number of base pairs and compared with each other. P values were calculated by Fisher’s exact test. (E) Biallelic GL variants of SAMD9L. Representative view of 2 independent GL SAMD9L variants (Tyr705Pro, Ser728Pro) in a patient (UPN029). Variant allele frequencies and counts of sequence reads in GL samples (CD3 positive lymphocyte) are shown in boxes. (F) Landscape of somatic mutations and CNAs in adult MDS patients with GL SAMD9/SAMD9L variants. Type of mutations, cytogenetics, and diagnosis, together with the number of somatic mutations/CNAs, are color coded as indicated. (G) A patient (UPN005) with a GL frameshift SAMD9L variant (Leu1323fs) and −7 simultaneously. Variant allele frequencies and counts of sequence reads in GL (CD3 positive lymphocyte) and tumor (bone marrow) are shown in boxes.
Figure 2.
Figure 2.
Functional impact of SAMD9/SAMD9L mutants. (A) Doxycycline-induced expression of rTagRFP-SAMD9L protein in HEK293 cells. (B-C) Cell proliferation curves of HEK293 cells with inducible expression (wild-type [WT] or mutant) of SAMD9/SAMD9L proteins; SAMD9 (B), SAMD9L (C). SAMD9/SAMD9L WT protein (black circles) had slower cell growth than noninduced HEK293 cells (white circles). GOF SAMD9L variant His880Glu was used as a positive control of slower cell growth than WT. Growth curve data are representative of 3 independent assays performed in triplicate. Error bars indicate standard errors. (D) Model of SAMD9/SAMD9L GL variant’s physiology in MDS. GOF SAMD9/SAMD9L GL variants suppress proliferation of human hematopoietic stem/progenitor cells (HSPCs), could be removed by genetic reversions that are rapidly selected for in pediatric MDS without additional secondary hits (upper panel). In contrast, LOF SAMD9/SAMD9L GL variants found in adult MDS cases increase cell proliferation of HSPCs, were not subject to somatic reversion, and were accompanied by additional secondary hits. The greater number of hits needed explains the longer latency in adult MDS (lower panel).
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References

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