The BTG/TOB family protein TIS21 regulates stage-specific proliferation of developing thymocytes.

As thymocytes undergo differentiation in the thymus, they progress through distinct phases of quiescence and proliferation. Identifying cellular mechanisms that maintain thymocytes in a non-dividing state is critical to fully understand T cell development. A member of the B cell translocation gene/transducer of ErbB-2 (BTG/TOB) family of anti-proliferative proteins was identified as a key mediator of the quiescent state in peripheral anergic and unstimulated T cells. Here, we demonstrate that the BTG/TOB family member TPA-inducible sequence 21 (TIS21) is expressed in quiescent CD44+ CD25- early progenitor thymocytes and CD44- CD25+ cells prior to TCR beta-selection. However, TIS21 expression is decreased in proliferating CD25+ CD44+ progenitor thymocytes and CD25(low) CD44- beta-selected cells, suggesting that its regulated expression may enable thymocytes to remain quiescent in the absence of mitogenic signals. We addressed the role of TIS21 in regulating thymocyte stage-specific expansion by ectopically expressing TIS21 in developing thymocytes and hematopoietic progenitors. Dysregulated expression of TIS21 inhibited the expansion of thymocytes even in the presence of endogenous mitogenic signals, while thymocyte differentiation was unimpeded. These findings imply that the intracellular mechanisms regulating thymocyte differentiation and proliferation, which are induced downstream of developmental cues, function independently during early T cell development.

High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia.

The detection of leukemia cells on newborn genetic screening cards ("Guthrie cards") of a small group of patients and several sets of identical twins developing acute lymphoblastic leukemia (ALL) with identical phenotypic and chromosomal markers has provided evidence that childhood ALL cases may arise in utero. We conducted a retrospective study of a randomly selected group of childhood B-precursor ALL patients to determine the frequency of the presence of "leukemic" clones prenatally in ALL cases by testing newborn screening cards. The 17 ALL patients analyzed had a median age of 46 months (range, 18 months to 13 years) and had median presenting white blood cell (WBC) counts of 10 950/microL (range, 2900-70 300/microL) at diagnosis. A clonal rearrangement of the immunoglobulin heavy chain (IgH) gene was identified in diagnostic lymphoblasts and sequenced and patient-specific primers were used to amplify DNA from blood samples on the patient's newborn screening cards. Twelve of the 17 (71%) analyzed newborn cards had detectable IgH rearrangements amplified by seminested polymerase chain reaction. DNA sequencing confirmed that the IgH rearrangements detected matched the IgH sequences identified from diagnostic leukemia cells, indicating the presence of a "leukemic" clone at birth. There were no differences in age or presenting WBC counts between the cases with or without positive newborn screening cards. All 6 patients with hyperdiploid ALL had detectable "leukemic" clones on their cards. The results of our study support the notion that a high proportion of childhood B-precursor ALL cases arise in utero, although postnatal events are also important factors in leukemogenesis.