Molecular Heterogeneity of the PML Gene Rearrangement in Acute Promyelocytic Leukemia: Prevalence and Clinical Significance

Overview

Journal Jpn J Cancer Res

Specialty Oncology

Date 1993 Mar 1

PMID 8387477

Authors

H Fukutani

T Naoe

H Yoshida

S Yamamori

R Ohno

Affiliations

Soon will be listed here.

Abstract

We determined the breakpoints of the RAR-alpha and PML genes in acute promyelocytic leukemia (APL) cells from 40 patients using Southern blot analysis. We also analyzed the relationship between the location of breakpoints, the clinical features of APL and the response to all-trans retinoic acid (ATRA). While the breakpoints of the RAR-alpha gene were consistently within intron 2, we found two major clusters in the breakpoints of the PML gene. The two breakpoint clusters in the PML gene were separated by 10 kb; 5' breakpoints were in intron 3, and 3' breakpoints were around introns 5 and 6. Twenty percent of the patients had 5' breakpoints in the PML gene and 70% had 3' breakpoints. No rearrangement was observed in the remaining 10% of patients in spite of the presence of t(15;17) translocation. There was no relationship between the location of the PML breakpoints, the clinical features at diagnosis and the response to ATRA.

References

Kastner P, Perez A, Lutz Y, Rochette-Egly C, Gaub M, Durand B . Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins. EMBO J. 1992; 11(2):629-42. PMC: 556495. DOI: 10.1002/j.1460-2075.1992.tb05095.x. View

Tong J, Dong S, Geng J, Huang W, Wang Z, Sun G . Molecular rearrangements of the MYL gene in acute promyelocytic leukemia (APL, M3) define a breakpoint cluster region as well as some molecular variants. Oncogene. 1992; 7(2):311-6. View

Borrow J, Goddard A, Sheer D, Solomon E . Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science. 1990; 249(4976):1577-80. DOI: 10.1126/science.2218500. View

de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A . The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991; 66(4):675-84. DOI: 10.1016/0092-8674(91)90113-d. View

Warrell Jr R, Frankel S, Miller Jr W, Scheinberg D, Itri L, Hittelman W . Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). N Engl J Med. 1991; 324(20):1385-93. DOI: 10.1056/NEJM199105163242002. View

Bennett J, Catovsky D, Daniel M, Flandrin G, GALTON D, Gralnick H . Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med. 1985; 103(4):620-5. DOI: 10.7326/0003-4819-103-4-620. View

Castaigne S, Chomienne C, Daniel M, Ballerini P, Berger R, Fenaux P . All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical results. Blood. 1990; 76(9):1704-9. View

Kurzrock R, Shtalrid M, Romero P, Kloetzer W, Talpas M, Trujillo J . A novel c-abl protein product in Philadelphia-positive acute lymphoblastic leukaemia. Nature. 1987; 325(6105):631-5. DOI: 10.1038/325631a0. View

Neri A, Barriga F, Knowles D, Magrath I, Dalla-Favera R . Different regions of the immunoglobulin heavy-chain locus are involved in chromosomal translocations in distinct pathogenetic forms of Burkitt lymphoma. Proc Natl Acad Sci U S A. 1988; 85(8):2748-52. PMC: 280076. DOI: 10.1073/pnas.85.8.2748. View

10.

Osada H, Seto M, Ueda R, Emi N, Takagi N, Obata Y . bcl-2 gene rearrangement analysis in Japanese B cell lymphoma; novel bcl-2 recombination with immunoglobulin kappa chain gene. Jpn J Cancer Res. 1989; 80(8):711-5. PMC: 5917842. DOI: 10.1111/j.1349-7006.1989.tb01702.x. View

11.

Kakizuka A, Miller Jr W, Umesono K, Warrell Jr R, Frankel S, Murty V . Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991; 66(4):663-74. DOI: 10.1016/0092-8674(91)90112-c. View

12.

Chomienne C, Ballerini P, Balitrand N, Daniel M, Fenaux P, Castaigne S . All-trans retinoic acid in acute promyelocytic leukemias. II. In vitro studies: structure-function relationship. Blood. 1990; 76(9):1710-7. View

13.

Miller Jr W, Kakizuka A, Frankel S, Warrell Jr R, DEBLASIO A, Levine K . Reverse transcription polymerase chain reaction for the rearranged retinoic acid receptor alpha clarifies diagnosis and detects minimal residual disease in acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 1992; 89(7):2694-8. PMC: 48728. DOI: 10.1073/pnas.89.7.2694. View

14.

Lemons R, Eilender D, Waldmann R, Rebentisch M, Frej A, Ledbetter D . Cloning and characterization of the t(15;17) translocation breakpoint region in acute promyelocytic leukemia. Genes Chromosomes Cancer. 1990; 2(2):79-87. DOI: 10.1002/gcc.2870020202. View

15.

Petkovich M, Brand N, Krust A, Chambon P . A human retinoic acid receptor which belongs to the family of nuclear receptors. Nature. 1987; 330(6147):444-50. DOI: 10.1038/330444a0. View

16.

Alcalay M, Zangrilli D, Pandolfi P, Longo L, Mencarelli A, Giacomucci A . Translocation breakpoint of acute promyelocytic leukemia lies within the retinoic acid receptor alpha locus. Proc Natl Acad Sci U S A. 1991; 88(5):1977-81. PMC: 51149. DOI: 10.1073/pnas.88.5.1977. View

17.

Chen S, Zhu Y, Tong J, Dong S, Huang W, Chen Y . Rearrangements in the second intron of the RARA gene are present in a large majority of patients with acute promyelocytic leukemia and are used as molecular marker for retinoic acid-induced leukemic cell differentiation. Blood. 1991; 78(10):2696-701. View

18.

de The H, Chomienne C, Lanotte M, Degos L, Dejean A . The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature. 1990; 347(6293):558-61. DOI: 10.1038/347558a0. View

19.

Shiramizu B, Barriga F, Neequaye J, Jafri A, Dalla-Favera R, Neri A . Patterns of chromosomal breakpoint locations in Burkitt's lymphoma: relevance to geography and Epstein-Barr virus association. Blood. 1991; 77(7):1516-26. View

20.

Goddard A, Borrow J, Freemont P, Solomon E . Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science. 1991; 254(5036):1371-4. DOI: 10.1126/science.1720570. View