Spontaneous remission and loss of monosomy 7: a window of opportunity for young children with SAMD9L syndrome.

Monosomy 7 is the most common cytogenetic abnormality in pediatric myelodysplastic syndrome (MDS) and associated with a high risk of disease progression. However, in young children, spontaneous loss of monosomy 7 with concomitant hematologic recovery has been described, especially in the presence of germline mutations in SAMD9 and SAMD9L genes. Here, we report on our experience of close surveillance instead of upfront hematopoietic stem cell transplantation (HSCT) in seven patients diagnosed with SAMD9L syndrome and monosomy 7 at a median age of 0.6 years (0.4-2.9). Within 14 months from diagnosis, three children experienced spontaneous hematological remission accompanied by a decrease in monosomy 7 clone size. Subclones with somatic SAMD9L mutations in cis were identified in five patients, three of whom attained hematological remission. Two patients acquired RUNX1 and EZH2 mutations during the observation period, of whom one progressed to MDS with excess of blasts (MDS-EB). Four patients underwent allogeneic HSCT at a median time of 26 months (14-40) from diagnosis for MDS-EB, necrotizing granulomatous lymphadenitis, persistent monosomy 7, and severe neutropenia. At last follow-up, six patients were alive, while one passed away due to transplant-related causes. These data confirm previous observations that monosomy 7 can be transient in young children with SAMD9L syndrome. However, they also indicate that delaying HSCT poses a substantial risk of severe infection and disease progression. Finally, surveillance of patients with SAMD9L syndrome and monosomy 7 is critical to define the evolving genetic landscape and to determine the appropriate timing of HSCT.

[1]  E. Gilson,et al.  Clonal hematopoiesis driven by chromosome 1q/MDM4 trisomy defines a canonical route toward leukemia in Fanconi anemia. , 2023, Cell stem cell.

[2]  M. Rudelius,et al.  The International Consensus Classification (ICC) of hematologic neoplasms with germline predisposition, pediatric myelodysplastic syndrome, and juvenile myelomonocytic leukemia , 2022, Virchows Archiv.

[3]  S. Ha,et al.  Spontaneous resolution of refractory cytopenia of childhood with monosomy 7 in an infant without an identifiable genetic cause , 2022, Pediatric blood & cancer.

[4]  Shondra M. Pruett-Miller,et al.  Gain-of-function mutations in RPA1 cause a syndrome with short telomeres and somatic genetic rescue , 2021, Blood.

[5]  J. Tchinda,et al.  Clinical evolution, genetic landscape and trajectories of clonal hematopoiesis in SAMD9/SAMD9L syndromes , 2021, Nature Medicine.

[6]  T. Dörk,et al.  Cancer in Children With Fanconi Anemia and Ataxia-Telangiectasia—A Nationwide Register-Based Cohort Study in Germany , 2021, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  D. Tillo,et al.  ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome , 2021, Blood advances.

[8]  J. Tchinda,et al.  Association of Unbalanced Translocation der(1;7) with Germline GATA2 Mutations. , 2021, Blood.

[9]  P. Revy,et al.  Somatic genetic rescue of a germline ribosome assembly defect , 2021, Nature Communications.

[10]  M. Boroni,et al.  Somatic genomic variants in refractory cytopenia of childhood , 2021, Pediatric Hematology Oncology Journal.

[11]  J. Surrallés,et al.  Natural gene therapy by reverse mosaicism leads to improved hematology in Fanconi anemia patients , 2021, American journal of hematology.

[12]  Shondra M. Pruett-Miller,et al.  Pediatric MDS and bone marrow failure-associated germline mutations in SAMD9 and SAMD9L impair multiple pathways in primary hematopoietic cells , 2021, Leukemia.

[13]  Nicholas D. Camarda,et al.  Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome , 2021, Nature Communications.

[14]  S. Izraeli,et al.  Incorporation of somatic panels for the detection of haematopoietic transformation in children and young adults with leukaemia predisposition syndromes and with acquired cytopenias , 2020, British journal of haematology.

[15]  A. Fischer,et al.  Somatic genetic rescue in Mendelian haematopoietic diseases , 2019, Nature Reviews Genetics.

[16]  G. Webersinke,et al.  Somatic mosaic monosomy 7 and UPD7q in a child with MIRAGE syndrome caused by a novel SAMD9 mutation , 2019, Pediatric blood & cancer.

[17]  M. Loh,et al.  Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes. , 2018, JCI insight.

[18]  Hiroaki Honda,et al.  The enigma of monosomy 7. , 2018, Blood.

[19]  M. McNerney,et al.  Gene dosage effect of CUX1 in a murine model disrupts HSC homeostasis and controls the severity and mortality of MDS. , 2018, Blood.

[20]  J. Soulier,et al.  A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. , 2018, Blood.

[21]  M. Boerries,et al.  Constitutional SAMD9L mutations cause familial myelodysplastic syndrome and transient monosomy 7 , 2017, Haematologica.

[22]  T. Fioretos,et al.  Gain-of-function SAMD9L mutations cause a syndrome of cytopenia, immunodeficiency, MDS, and neurological symptoms. , 2017, Blood.

[23]  G. Kokai,et al.  Somatic mutations and progressive monosomy modify SAMD9-related phenotypes in humans , 2017, The Journal of clinical investigation.

[24]  M. Wlodarski,et al.  Mutational landscape in children with myelodysplastic syndromes is distinct from adults: specific somatic drivers and novel germline variants , 2017, Leukemia.

[25]  J. Klco,et al.  The genomic landscape of pediatric myelodysplastic syndromes , 2016, Nature Communications.

[26]  J. Biegel,et al.  Clonal hematopoiesis in patients with dyskeratosis congenita , 2016, American journal of hematology.

[27]  Deborah Nickerson,et al.  Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L. , 2016, American journal of human genetics.

[28]  H. Okano,et al.  SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7 , 2016, Nature Genetics.

[29]  A. Iwama,et al.  Ezh2 loss in hematopoietic stem cells predisposes mice to develop heterogeneous malignancies in an Ezh1-dependent manner. , 2015, Blood.

[30]  T. Golub,et al.  The Genomic Landscape of Juvenile Myelomonocytic Leukemia , 2015, Nature Genetics.

[31]  Bale,et al.  Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology , 2015, Genetics in Medicine.

[32]  Zhen Zhao,et al.  MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia. , 2014, Cancer cell.

[33]  D. Steinemann,et al.  Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. , 2013, Blood.

[34]  T. Suda,et al.  Haploinsufficiency of SAMD9L, an endosome fusion facilitator, causes myeloid malignancies in mice mimicking human diseases with monosomy 7. , 2013, Cancer cell.

[35]  Jesse J. Salk,et al.  Detection of ultra-rare mutations by next-generation sequencing , 2012, Proceedings of the National Academy of Sciences.

[36]  R. Pfundt,et al.  Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita. , 2012, American journal of human genetics.

[37]  J. Harbott,et al.  Complex karyotype newly defined: the strongest prognostic factor in advanced childhood myelodysplastic syndrome. , 2010, Blood.

[38]  D. Johnston,et al.  Spontaneous remission of myelodysplastic syndrome with monosomy 7 in a young boy. , 2008, Cancer genetics and cytogenetics.

[39]  S. Raimondi,et al.  Monosomy 7 and deletion 7q in children and adolescents with acute myeloid leukemia: an international retrospective study. , 2007, Blood.

[40]  J. Harbott,et al.  Refractory anemia in childhood: a retrospective analysis of 67 patients with particular reference to monosomy 7. , 2003, Blood.

[41]  J. Harbott,et al.  Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7 , 1999, Leukemia.

[42]  A. Borkhardt,et al.  Spontaneous hematological remission in a boy with myelodysplastic syndrome and monosomy 7. , 1994, Leukemia.