Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia.
Collectively, these results suggest that Fancd2 restricts mitochondrial activity through regulation of mitochondrial translation, and that augmented mitochondrial translation and mitochondrial respiration may contribute to HSC defect and bone marrow failure in FA.
Notably, similar to a subset of FA genes that act downstream of FANCD2, biallelic mutation of XRCC2/FANCU has not been associated with bone marrow failure.
Fanconi Anemia (FA) is an autosomal recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure and Fanconi anemia complementation group A (FANCA) is also a potential breast and ovarian cancer susceptibility gene.
However, patients with FANCG mutations had inferior BMF-free survival and received hematopoietic stem cell transplantation (HSCT) at a younger age than those with FANCA mutations.
Collectively, these findings demonstrate that mutations in DNAJC21 cause a cancer-prone BMF syndrome due to corruption of early nuclear rRNA biogenesis and late cytoplasmic maturation of the 60S subunit.
We conclude that in spite of the well-documented in vitro apoptotic tendency of FA-phenotype hematopoietic cells, the in vivo administration of IFN-gamma with and without subsequent fas ligation does not induce bone marrow failure in FANCC(-/-) (129SvJ strain) mice.
One dose of filgrastim 300 μg was administered subcutaneously on day 6 in response to the pancytopenia, after which the platelet, hemoglobin, and WBC values stabilized for a day and then generally declined.
A 50-year-old man with large granular lymphocytic leukemia (CD3+, CD8+) complicated by severe pancytopenia and life-threatening infections refractory to therapy with prednisone, methotrexate, cyclosporine, and G-CSF is described.
Bone marrow failure was defined as absolute neutrophil count (ANC) <500 neutrophils/μL day 42 after infusion of CAR-T cells or filgrastim support to reach that number.
We also report the successful management of pancytopenia and oral ulcers with combination therapy of leucovorin and granulocyte colony-stimulating factor.
The pancytopenia was diagnosed as an adverse effect of nivolumab; filgrastim (75 μg/day), steroid-pulse therapy (intravenous methylprednisolone: 500 mg/day), and subsequently intravenous prednisolone (50 mg/day) were administered.
We propose the term MECOM-associated syndrome for this heterogeneous hereditary disease and inclusion of <i>MECOM</i> sequencing in the diagnostic workup of congenital bone marrow failure.
We report for the first time a constitutional deletion encompassing the EVI1 and MDS1 genes in a human, and argue that the deletion causes congenital bone marrow failure in this patient.
We also found mutations in genes seldom reported in inherited BMF (IBMF), such as <i>SAMD9</i> and <i>SAMD9L</i> (N = 16 of the 86 patients, 18.6%), <i>MECOM/EVI1</i> (N = 6, 7.0%), and <i>ERCC6L2</i> (N = 7, 8.1%), each of which was associated with a distinct natural history; <i>SAMD9</i> and <i>SAMD9L</i> patients often experienced transient aplasia and monosomy 7, whereas <i>MECOM</i> patients presented early-onset severe aplastic anemia, and <i>ERCC6L2</i> patients, mild pancytopenia with myelodysplasia.
Our results showed that patients, homozygous for the FANCG founder mutation, present with severe cytopenia but progress to bone marrow failure at similar ages to other individuals affected with FA of heterogeneous genotype.
However, patients with FANCG mutations had inferior BMF-free survival and received hematopoietic stem cell transplantation (HSCT) at a younger age than those with FANCA mutations.
Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS).
Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS).
Administration of EPO improved 30-day survival, alleviated TBI-induced myelosuppression and pancytopenia, by augmenting lymphocytes and other white blood cells in the peripheral blood of rats, while bone marrow and spleen cellularity were restored.
Here we studied the prevalence of TERC and TERT gene mutations and of telomere shortening in an unselected population of patients with BMF at our medical center and in a selected group of patients referred from outside institutions.