Chromosomal translocations of the human mixed-lineage leukemia (MLL) gene have been analyzed for more than 20 yr at the molecular level. So far, we have collected about 80 direct MLL fusions (MLL-X alleles) and about 120 reciprocal MLL fusions (X-MLL alleles). The reason for the higher amount of reciprocal MLL fusions is that the excess is caused by 3-way translocations with known direct fusion partners. This review is aiming to propose a solution for an obvious problem, namely why so many and completely different MLL fusion alleles are always leading to the same leukemia phenotypes (ALL, AML, or MLL). This review is aiming to explain the molecular consequences of MLL translocations, and secondly, the contribution of the different fusion partners. A new hypothesis will be posed that can be used for future research, aiming to find new avenues for the treatment of this particular leukemia entity.
Alleles ; Chromosomes, Human, X ; Epigenesis, Genetic ; Humans ; Leukemia/classification/*genetics/pathology ; Myeloid-Lymphoid Leukemia Protein/chemistry/genetics ; Protein Structure, Tertiary ; Translocation, Genetic

No abstract available.
Adult ; Antigens, CD4/*metabolism ; Antigens, CD56/*metabolism ; Bone Marrow/metabolism/pathology ; Dendritic Cells/cytology/*metabolism ; Diagnostic Errors ; Exons ; Female ; Flow Cytometry ; Gene Rearrangement ; Hematologic Neoplasms/diagnosis ; Histone-Lysine N-Methyltransferase/genetics ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Leukemia, Myeloid, Acute/*diagnosis ; Male ; Middle Aged ; Myeloid-Lymphoid Leukemia Protein/genetics ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, DNA ; Transcription Factors/genetics ; Translocation, Genetic

Diseases in Twins ; Female ; Gene Rearrangement ; Humans ; Infant ; Male ; Myeloid-Lymphoid Leukemia Protein ; genetics ; Oncogene Proteins, Fusion ; genetics ; Polymerase Chain Reaction ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; pathology ; Twins, Monozygotic

Diagnosis, Differential ; Humans ; Killer Cells, Natural ; pathology ; Leukemia, Lymphoid ; diagnosis ; pathology

B-Lymphocytes ; Child ; Humans ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; immunology ; Precursor Cells, B-Lymphoid ; pathology

During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.
Animals ; Breast Neoplasms ; genetics ; pathology ; physiopathology ; Cell Transformation, Neoplastic ; Chromatin ; genetics ; metabolism ; Epigenesis, Genetic ; physiology ; Epithelial Cells ; cytology ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Histone-Lysine N-Methyltransferase ; Humans ; Mammary Glands, Animal ; cytology ; growth & development ; Mammary Glands, Human ; cytology ; growth & development ; Myeloid-Lymphoid Leukemia Protein ; genetics ; physiology ; Polycomb-Group Proteins ; genetics ; physiology ; Receptors, Estrogen ; metabolism

Normal hematopoietic B progenitor cells are similar with acute B lymphoblastic leukemia (ALL) cells in terms of morphology and immunophenotypes which easily result in misdiagnosis of diseases. This study was purposed to explore the importance of B progenitor cell (BPC) level in differential diagnosis of hematologic diseases. A total of 664 specimens including 87 specimens from patients with non-malignant hematologic diseases as control and 577 specimens from AL patients in different progressive stage were analyzed. Out of 577 specimens 26 were collected from ALL patients, 261 were collected from B-ALL, 290 were collected from AML. The relation of different clinical status (new diagnosis, remission, relapse), age and degree of leukemia cell involvement with hematopoietic BPC level were analyzed through identification of CD34/CD10/CD19/CD45 antibody combination and quantification of hematopoietic BPC. The results indicated that (1) CD45 distributed from positive to weak positive, and with very low side scatter. The early hematopoietic BPC expressed CD34⁺, along with increasing of cell maturation, the CD34 expression gradually disappeared, while CD19 and CD10 showed positive in whole stage of hemaropoietic BPC, and early CD10 highly was expressed. (2) the mean percentage of hematopoietic BPC was 1.36% in control group, 0.60% in T-ALL, 1.39% in B-ALL and 0.80% in AML; the detected rate of hematopoietic BPC in control, T-ALL, B-ALL and AML were 87.4%, 61.5%, 83.5%, 75.9%, respectively; the mean percentage of hematopoietic BPC was 0.37% at new diagnosis, 1.66% in remission and 0.55% in relapse. (3) along with increase of age, the hematopoietic BPC level generally disclined. (4) specimens >5% hematopoietic BPC were mainly found in remission stage of leukemia patients. It is concluded that the hematopoietic BPC are present in malignant and non-malignant hematologic diseases. The changes of hematopoietic BPC level correlate with disease state, age and leukemia cell involvement. The increased hematopoietic BPC level are observed most often in the patients with remission after themotherapy. It should be carefully to diagnose and discriminate between malignant and benign cells with double positive CD19 and CD10. Use of multiparametric flow cytometry and optimal antibody combination are important for discriminating hematopoietic BPC from minor residual disease and accuratly diagnosing diseases and evaluating curative effectiveness.
Acute Disease ; Cell Differentiation ; Flow Cytometry ; Hematopoietic System ; Humans ; Immunophenotyping ; Leukemia ; pathology ; Neoplasm Recurrence, Local ; Neoplasm, Residual ; Precursor Cells, B-Lymphoid ; pathology

This study was aimed to explore the effects of insulin on expression of insulin receptor (IR) and insulin-like growth factor-I receptor (IGF-IR) in Reh cells and promoting effect on proliferation of Reh cells. The proliferation of Reh cells were evaluated by CCK-8 assay. The expression levels of IR and IGF-IR mRNA in Reh cells at different times were detected by real-time quantitative polymerase chain reaction. The results showed that insulin promoted the proliferation of Reh cells in dose- and time-dependent manners. Compared with the control group, insulin promoted the proliferation of Reh cells obviously (P < 0.05). When Reh cells were treated with insulin 10(-9) mol/L for 24, 48 and 72 h, the relative quantity of IR expression (2(-ΔCt1)/2(-ΔCt2)) was 2.2520 ± 0.7431, 1.9956 ± 0.9692 and 3.9766 ± 1.3189, respectively, the relative quantity of IGF-IR expression was 1.0803 ± 0.2238, 1.6026 ± 0.6158 and 3.1013 ± 0.1008, respectively, compared with the control group. The expression levels of IR and IGF-IR mRNA in Reh cells treated with insulin were obviously increased compared with the control group. It is concluded that insulin promotes the proliferation of Reh cells. The high expression levels of IR and IGF-IR may closely related with the growth of leukemia cells.
Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; Insulin ; pharmacology ; Leukemia, Lymphoid ; metabolism ; pathology ; Receptor, IGF Type 1 ; metabolism ; Receptor, Insulin ; metabolism

The chromosome band 11q23 is a common target region of chromosomal translocation in different types of leukemia, including infantile leukemia and therapy-related leukemia. The target gene at 11q23, MLL, is disrupted by the translocation and becomes fused to various translocation partners. We report a case of AML with a rare 3-way translocation involving chromosomes 1, 9, and 11: t(1;9;11)(p34.2;p22;q23). A 3-yr-old Korean girl presented with a 5-day history of fever. A diagnosis of AML was made on the basis of the morphological evaluation and immunophenotyping of bone marrow specimens. Flow cytometric immunophenotyping showed blasts positive for myeloid lineage markers and aberrant CD19 expression. Karyotypic analysis showed 46,XX,t(1;9;11)(p34.2;p22;q23) in 19 of the 20 cells analyzed. This abnormality was involved in MLL/MLLT3 rearrangement, which was confirmed by qualitative multiplex reverse transcription-PCR and interphase FISH. She achieved morphological and cytogenetic remission after 1 month of chemotherapy and remained event-free for 6 months. Four cases of t(1;9;11)(v;p22;q23) have been reported previously in a series that included cases with other 11q23 abnormalities, making it difficult to determine the distinctive clinical features associated with this abnormality. To our knowledge, this is the first description of t(1;9;11) with clinical and laboratory data, including the data for the involved genes, MLL/MLLT3.
Antigens, CD19/metabolism ; Bone Marrow Cells/pathology ; Child, Preschool ; Chromosomes, Human, Pair 1 ; Chromosomes, Human, Pair 11 ; Chromosomes, Human, Pair 9 ; Female ; Humans ; Immunophenotyping ; In Situ Hybridization, Fluorescence ; Karyotyping ; Leukemia, Myeloid, Acute/*diagnosis/genetics/immunology ; Myeloid-Lymphoid Leukemia Protein/*genetics ; Nuclear Proteins/*genetics ; *Translocation, Genetic

ALL with MLL gene rearrangement secondary to chemotherapy has been rarely reported. We report a case of therapy-related ALL (t-ALL) with MLL gene rearrangement in a patient who had undergone treatment for breast cancer. A 60-yr-old woman with breast cancer underwent breast-conserving surgery followed by 6 cycles of adjuvant chemotherapy (cyclophosphamide, epirubicin, and fluorouracil) and radiation therapy (dose, 5,040 cGy to the left breast and a 1,000 cGy boost to the tumor bed). A follow-up examination performed 14 months after the chemotherapy revealed no evidence of breast malignancy. However, the patient's complete blood cell count indicated acute leukemia: white blood cell count, 174.1x10(9)/L with 88% blasts; Hb level, 12.5 g/dL; and platelet count, 103.0x10(9)/L. Examination of the bone marrow aspirate smear revealed a high percentage of blasts (85.1% of all nucleated cells); the blasts showed a pro-B immunophenotype and were positive for CD19, CD79a, HLA-DR, CD34, and terminal deoxynucleotidyl transferase (TdT). Cytogenetic and FISH analyses revealed t(4;11)(q21;q23) and MLL gene rearrangement, respectively. The patient received induction chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone and achieved complete remission. Following consolidation chemotherapy, she underwent allogenic peripheral blood stem cell transplantation and has been clinically stable. To our knowledge, this is the first reported case of t-ALL with MLL gene rearrangement following treatment of breast cancer in Korea.
Antibiotics, Antineoplastic/therapeutic use ; Blood Cell Count ; Bone Marrow/pathology ; Breast Neoplasms/*drug therapy/radiotherapy ; Chemotherapy, Adjuvant ; Combined Modality Therapy ; Cyclophosphamide/therapeutic use ; Cytogenetic Analysis ; Epirubicin/therapeutic use ; Female ; Fluorouracil/therapeutic use ; Gene Rearrangement ; Hematopoietic Stem Cell Transplantation ; Humans ; In Situ Hybridization, Fluorescence ; Myeloid-Lymphoid Leukemia Protein/*genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*etiology/genetics/pathology ; *Translocation, Genetic