Gene-expression profiles and oncogenes in pediatric T-cell acute lymphoblastic leukemia

Blood consists of serum and three other main ingredients: erythrocytes (red blood cells), thrombocytes (platelets) and leukocytes (white blood cells). Leukocytes normally compose less than 1% of the blood volume but have important functions in our defense against foreign and endogenous pathogens. Many different leukocytes can be distinguished, the main types being lymphocytes (~75% T-cells, ~25% B-cells), monocytes and granulocytes. All these different blood cells arise through distinct and tightly controlled developmental stages from hematopoietic precursor cells, which reside in the bone marrow and thymus (Figure 1). However, sequential mutations, chromosomal rearrangements and epigenetic changes can cause a precursor cell to be blocked from further differentiation and to start proliferate in a uncontrollable manner which results in cancer. Uncontrolled proliferation of blood precursor cells is called leukemia. Different types of leukemia are distinguished based on their lineage of origin; myeloid or lymphoblastic leukemia. Lymphoblastic leukemia can be further divided into Bcell precursor (BCP) or T-cell lymphoblastic leukemia. In acute lymphoblastic leukemia malignant cells are arrested at a relative immature stage whereas in chronic lymphocytic leukemia, cells have a more differentiated phenotype

Features of Pavement Damage due to Hyogo-ken Nanbu Earthquake

Translocation of the LYL1 oncogene are rare in T-cell acute lymphoblastic leukemia, whereas the homologous TAL1 gene is rearranged in approximately 20% of patients. Previous gene-expression studies have identified an immature T-cell acute lymphoblastic leukemia subgroup with high LYL1 expression in the absence of chromosomal aberrations. Molecular characterization of a t(7;19)(q34;p13) in a pediatric T-cell acute lymphoblastic leukemia patient led to the identification of a translocation between the TRB@ and LYL1 loci. Similar to incidental T-cell acute lymphoblastic leukemia cases with synergistic, double translocations affecting TAL1/2 and LMO1/2 oncogenes, this LYL1-translocated patient also had an LMO2 rearrangement pointing to onco-genic cooperation between LYL1 and LMO2. In hierarchical cluster analyses based on gene-expression data, this sample consi

Breakpoint sites disclose the role of the V(D)J recombination machinery in the formation of T-cell receptor (TCR) and non-TCR associated aberrations in T-cell acute lymphoblastic leukemia

Aberrant recombination between T-cell receptor genes and oncogenes gives rise to chromosomal translocations that are genetic hallmarks in several subsets of human T-cell acute lymphoblastic leukemias. The V(D)J recombination machinery has been shown to play a role in the formation of these T-cell receptor translocations. Other, non-T-cell receptor chromosomal aberrations, such as SIL-TAL1 deletions, have likewise been recognized as V(D)J recombination associated aberrations. Despite the postulated role of V(D)J recombination, the extent of the V(D)J recombination machinery involvement in the formation of T-cell receptor and non-T-cell receptor aberrations in T-cell acute lymphoblastic leuke

Preimplantation genetic testing for Neurofibromatosis type 1:more than 20 years of clinical experience

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that affects the skin and the nervous system. The condition is completely penetrant with extreme clinical variability, resulting in unpredictable manifestations in affected offspring, complicating reproductive decision-making. One of the reproductive options to prevent the birth of affected offspring is preimplantation genetic testing (PGT). We performed a retrospective review of the medical files of all couples (n = 140) referred to the Dutch PGT expert center with the indication NF1 between January 1997 and January 2020. Of the couples considering PGT, 43 opted out and 15 were not eligible because of failure to identify the underlying genetic defect or unmet criteria for in vitro fertilization (IVF) treatment. The remaining 82 couples proceeded with PGT. Fertility assessment prior to IVF treatment showed a higher percentage of male infertility in males affected with NF1 compared to the partners of affected females. Cardiac evaluations in women with NF1 showed no contraindications for IVF treatment or pregnancy. For 67 couples, 143 PGT cycles were performed. Complications of IVF treatment were not more prevalent in affected females compared to partners of affected males. The transfer of 174 (out of 295) unaffected embryos led to 42 ongoing pregnancies with a pregnancy rate of 24.1% per embryo transfer. There are no documented cases of misdiagnosis following PGT in this cohort. With these results, we aim to provide an overview of PGT for NF1 with regard to success rate and safety, to optimize reproductive counseling and PGT treatment for NF1 patients.</p

NKL homeobox genes in leukemia.

NK-like (NKL) homeobox genes code for transcription factors, which can act as key regulators in fundamental cellular processes. NKL genes have been implicated in divergent types of cancer. In this review, we summarize the involvement of NKL genes in cancer and leukemia in particular. NKL genes can act as tumor-suppressor genes and as oncogenes, depending on tissue type. Aberrant expression of NKL genes is especially common in T-cell acute lymphoblastic leukemia (T-ALL). In T-ALL, 8 NKL genes have been reported to be highly expressed in specific T-ALL subgroups, and in ~30% of cases, high expression is caused by chromosomal rearrangement of 1 of 5 NKL genes. Most of these NKL genes are normally not expressed in T-cell development. We hypothesize that the NKL genes might share a similar downstream effect that promotes leukemogenesis, possibly due to mimicking a NKL gene that has a physiological role in early hematopoietic development, such as HHEX. All eight NKL genes posses a conserved Eh1 repressor motif, which has an important role in regulating downstream targets in hematopoiesis and possibly in leukemogenesis as well. Identification of a potential common leukemogenic NKL downstream pathway will provide a promising subject for future studies