Maya Thangavelu

dic(5;17): A recurring abnormality in malignant myeloid disorders associated with mutations of TP53

We have identified three unbalanced translocations involving chromosomes 5 and 17, der(5)t(5;17), der(17)t(5;17), and dic(5;17), in the malignant cells from 17 patients with myeloid neoplasms. Six patients had a primary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) de novo; ten patients had therapy‐related MDS and/or AML (t‐MDS/t‐AML), and one patient had chronic myelogenous leukemia in myeloid blast phase. Two of the six patients with MDS or AML de novo had extensive exposure to industrial solvents, and one patient had Seckel syndrome. The primary diagnoses for the ten patients with t‐MDS/t‐AML were breast carcinoma and Hodgkins disease in two patients each, and non‐Hodgkins lymphoma, multiple myeloma, chronic lymphocytic leukemia, ovarian carcinoma, thyroid carcinoma, and rhabdomyosarcoma in one patient each. Four patients had received both prior chemotherapy and radiotherapy, four others received prior chemotherapy only, and the remaining two patients only prior radiotherapy. Fluorescence in situ hybridization of centromere‐specific probes for chromosomes 5 and 17 revealed that a dicentric rearrangement was the most common (13/16 patients examined). The genetic consequences of these chromosomal rearrangements are partial monosomy for 5q and 17p. Two of six patients examined had point mutations in TP53, suggesting that loss of function of TP53 in addition to loss of a tumor suppressor gene on 5q may be involved in the pathogenesis of the malignant disease in some of these patients. Genes Chromosomes Cancer 20:282–291, 1997.

der(5)t(5;7)(q11.2;p11.2): A new recurring abnormality in malignant myeloid disorders☆

Complete or partial monosomy for the long arm of chromosomes 5 and/or 7 is frequently observed in malignant cells from patients with a therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute nonlymphocytic leukemia (t-ANLL). Partial monosomy is usually the result of a chromosomal deletion; however, unbalanced translocations have also been observed. We have identified one such translocation in three patients who had either t-ANLL or a primary MDS. The genetic consequences of this translocation [-5,-7,+der(5)t(5;7)(q11.2;p11.2)] are partial monosomy for the long arm of chromosome 5 and complete monosomy for the long arm of chromosome 7. Thus, this rearrangement may represent a new, recurring abnormality that is associated with malignant myeloid disorders.

A physical and genetic linkage map of the distal long arm of human chromosome 5

By in situ hybridization of probes for three cloned genes and eight genetically-linked polymorphic DNA markers, we have prepared a physical map of the distal long arm of chromosome 5. These results, together with the localizations of 11 genes and the genetic linkage map reported previously by us and by other investigators, represent a map that spans 55 cM.

Genetic Consequences of Chromosomal Abnormalities in the Myelodysplastic Syndromes

Hematologic malignant diseases have the distinction of being in the forefront both in the identification of recurring cytogenetic abnormalities and in the detailed analysis of these abnormalities at the molecular level. Perhaps the best examples are the translocations involving chromosomes 9 and 22, t(9;22)(q34;q11), in chronic myelogenous leukemia (CML), and the translocations involving chromosome 8 (q24) and chromosome 2 (p12), 14 (q32), or 22 (q11) in Burkitt’s lymphoma (BL). In CML, the ABL gene on chromosome 9 is translocated to chromosome 22 and is juxtaposed with the BCR gene. This results in the production of a structurally altered ABL protein, specifically, a fusion protein (BCR-ABL) that has an altered tyrosine kinase activity. In BL, the MYC gene (from chromosome 8) and the immunoglobulin genes (on chromosome 2, 14, or 22) are juxtaposed, resulting in the altered expression of the MYC gene.