ABSTRACT
The importance of HOXA genes in T-cell acute lymphoblastic leukemia (T-ALL) has recently been recognized. We report a novel chromosomal translocation in a T-ALL patient that maps upstream of the HOXA13 gene and downstream of the BCL11B/CTIP2 locus. Analysis of HOXA gene transcription demonstrated massive expression of HOXA13, whereas the other HOXA genes were unaffected. A genomic rearrangement of the HOXA locus associated with exclusive expression of HOXA13 was observed in a second patient. This situation resembles chromosomal translocations activating genes of the TLX/HOX11 family in T-ALLs. To compare the leukemogenic properties of HOXA13 to that of TLX proteins, cohorts of lethally irradiated mice were transplanted with bone marrow transduced with a retroviral vector expressing TLX3 or HOXA13. Cells transduced with TLX3 or HOXA13 could not be detected in the peripheral blood of mice post-transplantation and none of the mice developed malignancies. Cotransduction of the HOX cofactor MEIS1 with TLX3 or HOXA13 did not alter this outcome. However, in a myeloid clonogenic assay HOXA13 and TLX3 extended the proliferation of progenitors similarly to what was observed for TLX1. Altogether, our results strongly suggest the absolute requirement for cooperative events in association with homeobox gene up-regulation to induce T-cell leukemogenesis.
Subject(s)
Cell Transformation, Neoplastic/genetics , Homeodomain Proteins/genetics , Leukemia-Lymphoma, Adult T-Cell/genetics , Oncogene Proteins/genetics , Proto-Oncogene Proteins/genetics , Adolescent , Animals , Child , Homeodomain Proteins/physiology , Humans , Male , Mice , Mice, Inbred C57BL , Oncogene Proteins/physiology , Proto-Oncogene Proteins/physiologyABSTRACT
Since the RUNX1 gene contributes to megakaryopoiesis and acquired trisomy 21 is the most frequent numerical chromosome anomaly in acute megakaryoblastic leukemia (AMLK), a systematic study of RUNX1 abnormalities was performed by fluorescence in situ hybridization in AMLK patients. Four abnormalities were detected among 15 patients. One copy of RUNX1 was completeley or partially lost in three patients and translocated onto Xq24 in the fourth. The possible consequences of RUNX1 haploinsufficiency are discussed.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Gene Deletion , Leukemia, Megakaryoblastic, Acute/genetics , Adult , Aged , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Middle AgedABSTRACT
A systematic cytogenetic study was performed in 49 patients with polycythemia vera (PV) in order to investigate the occurrence of subtelomeric rearrangements of chromosome 20, the most frequently rearranged chromosome in this myeloproliferative disorder. Partial deletion of the long arm of chromosome 20 was observed in two patients and two cryptic translocations, t(1;20)(p36;q13) and t(18;20)(p11;q13) in two others, all previously treated. The localization of the breakpoints of the translocated 20 chromosomes was different in the two translocations, as shown by fluorescence in situ hybridization (FISH) to metaphase chromosomes using BAC clones. Although infrequent (2/49), cryptic translocations of chromosome 20 deserve to be detected as preliminary to identification of molecular defects in PV.
Subject(s)
Chromosomes, Human, Pair 20/genetics , Polycythemia Vera/genetics , Translocation, Genetic , Aged , Aged, 80 and over , Chromosome Deletion , Female , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Middle AgedABSTRACT
Most chromosomal translocations observed in T-cell acute lymphoblastic leukemia (T-ALL) often produce transcriptional activation of transcription factor oncogenes. Ectopic expression of the TLX3 (also known as HOX11L2) gene has been shown to be associated with a cryptic t(5;14)(q35;q32) translocation specific for a subtype of T-ALL. Here we report several examples of variant and alternative translocations resulting in expression of TLX3 in T-ALL, and we describe three of these translocations in detail. In particular, the CDK6 gene was rearranged in two t(5;7)(q35;q21) translocations. In two additional instances, fusion of the BCL11B (also known as CTIP2) and RANBP17/TLX3 loci were shown to result from subtle genomic insertion/deletion within these loci. This study further underscores that TLX3 expression in T-ALL is strongly associated with the presence of genomic rearrangements.
Subject(s)
Homeodomain Proteins/genetics , Oncogene Proteins/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adolescent , Blotting, Western , Cell Line, Tumor , Child , Child, Preschool , Chromosome Banding , Chromosomes/ultrastructure , Cyclin-Dependent Kinase 6 , Cyclin-Dependent Kinases/genetics , Female , Humans , Immunophenotyping , In Situ Hybridization, Fluorescence , Karyotyping , Male , Models, Genetic , Polymerase Chain Reaction , Proto-Oncogene Proteins , Translocation, Genetic , ran GTP-Binding Protein/genetics , ras Proteins/geneticsABSTRACT
Two patients with Ph-positive chronic myelocytic leukemia in erythroblastic transformation and rearrangement of the short arm of chromosome 18 are reported. Fluorescence in situ hybridization studies showed that the 18p rearrangement resulted from translocation of the main part of chromosome 22 long arm to 18p, including BCR-ABL1 fusion. The 18p abnormality resulted, thus, in loss of 18p and duplication of BCR-ABL1 in both patients. The possible relation to the erythroblastic type of blastic phase is briefly discussed. In addition an apparently intact germline ABL1 gene was duplicated and inserted into chromosome 6 at band p21 in one of these patients.
Subject(s)
Cell Transformation, Neoplastic , Chromosomes, Human, Pair 18/genetics , Erythrocytes/pathology , Fusion Proteins, bcr-abl/genetics , Gene Duplication , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Aged , Aged, 80 and over , Chromosome Aberrations , Chromosomes, Human, Pair 22/genetics , Female , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Middle Aged , Translocation, GeneticABSTRACT
Recurrent translocation t(8;21)(q22;q22) acute myeloid leukemia (AML) is often associated with secondary chromosome changes of which the clinical significance is not clear since they do not seem to impair the prognosis. Uncommon chromosome changes may lead to the identification of leukemogenetic factors associated with t(8;21) since the AML1/RUNX1-ETO fusion gene resulting from the translocation is thought to be unable alone to induce leukemia. We here report a patient with AML, t(8;21) and ring chromosome 8 resulting in partial chromosome 8 deletion. Another patient with partial 8q deletion has been previously reported. It is suggested that more attention be paid to the genes located in distal 8q in relation to leukemogenesis.
