BLOOD: 6.2.2014

BLOOD: Gadd45a regulates hematopoietic stem cell stress responses in mice

"Gadd45a has been involved in DNA damage response and in many malignancies, including leukemia. However, the function of Gadd45a in hematopoietic stem cells (HSCs) remains unknown. Here, we reported that Gadd45a-deficient (Gadd45a^−/−) mice showed a normal hematologic phenotype under homeostatic conditions. However, following 5-fluorouracil treatment, Gadd45a^−/− HSCs exhibited a faster recovery, associated with an increase in the proliferation rate. Interestingly, young Gadd45a^−/− HSCs showed enhanced reconstitution ability in serial transplantation. Following ionizing radiation (IR), young Gadd45a^−/− HSCs exhibited an increased resistance to IR-induced DNA damage, associated with a decrease in the apoptosis rate and delayed DNA repair. The significantly higher level of DNA damage in Gadd45a^−/− HSCs ultimately promoted B-cell leukemia in further transplanted recipient mice. In old mice, Gadd45a^−/− HSCs were functionally equal to wild-type HSCs but exhibited more DNA damage accumulation and increased sensitivity to IR than wild-type HSCs. In conclusion, Gadd45a plays a significant role in HSC stress responses. Gadd45a deficiency leads to DNA damage accumulation and impairment in apoptosis after exposure to IR, which increases the susceptibility of leukemogenesis."

http://bloodjournal.hematologylibrary.org/content/123/6/851.abstract

BLOOD: The evolution of cellular deficiency in GATA2 mutation

"Constitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56^bright NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8⁺ memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making."

http://bloodjournal.hematologylibrary.org/content/123/6/863.abstract