Rearrangements and aberrant expression of the retinoic acid receptor alpha gene in acute promyelocytic leukemias.

Abstract

Acute promyelocytic leukemia (APL;t M3 of the FAB 1 .1 classification) is a distinct, well-characterized clinical and morphological subtype of acute myeloid leukemia (AML) (1,2). It is cytogenetically distinguished by a reciprocal chromosome 15;17 translocation, which is present in 70-90% of cases and never seen in other AMLs or other types of malignancy (3, 4). Although the high frequency and specificity of the t(15;17), and the fact that it is often the only karyotypic aberration present (4), is strong evidence that it plays a crucial role in the pathogenesis ofAPL, the gene(s) directly involved in the chromosome 15 and 17 breakpoints have never been identified . We have previously shown that the APL chromosome 17 breakpoint lies between the c-erbB-2 and the retinoic acid receptor a (RARci) loci (5) . We report here the findings of RARct gene rearrangement and aberrant expression in APLs. Although acute promyelocytic leukemias (APLs) are consistently associated with a reciprocal chromosome 15;17 translocation, the gene(s) directly affected by the breakpoints have never been isolated. The chromosome 17 breakpoint maps to near the retinoic acid receptor a (RARa) locus. Investigation of20 APLs and a large series ofother neoplastic patients and normal controls revealed RARa gene rearrangements and aberrant transcripts only in the APL cases. These findings suggest that the RARce gene is involved in the APL chromosome 17 breakpoint, is implicated in leukemogenesis, and could be used as a marker for identifying leukemic promyelocytes. Materials and Methods Rearrangements and Aberrant Expression of theMolecular Studies. The K/S, IT, and P/R RARct cDNA probes were obtained by subcloning portions of the p63 plasmid (6) in 'Abbreviations used in this paper: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; BM, bone marrow ; RARa, retinoic acid receptor a.

Cooperativity between mutations in tyrosine kinases and in hematopoietic transcription factors in AML

“…Instead, translocations associated with AML almost invariably target transcription factors or components of the transcriptional activation apparatus. These include core binding factor (CBF), [14][15][16][17][18][19][20][21][22] retinoic acid receptor alpha, [23][24][25][26] HOX family members, [27][28][29] transcriptional modulatory proteins, such as MLL, [30][31][32][33][34][35][36][37] and transcriptional coactivating proteins, such as CBP, p300, and TIF2. 34,[37][38][39][40] CBF is a heterodimeric hematopoietic transcription factor that is exemplary of this broad class of translocation associated with AML.…”

True

“…The chromosomal break sites were isolated by four groups using distinct experimental approaches. [149][150][151][152] The two genes involved in t (15;17) are PML, coding for a putative novel transcription factor, on chromosome 15 [149][150][151][152] Table 16). Table 2 for complete sequence information.…”

Terminal megakaryocytic differentiation of TF-1 cells is induced by phorbol esters and thrombopoietin and is blocked by expression of PML/RARα fusion protein

“…At the molecular level APL is characterized by a specific chromosomal translocation involving chromosomes 15 and 17 [t(15;17)]. [3][4][5][6] As a consequence of this translocation a chimeric gene is formed encoding for the fusion protein PML/RAR␣. [7][8][9][10] RAR␣ encodes one of the retinoic acid receptors; 11,12 PML encodes a protein of unknown function localized in subnuclear structures called nuclear bodies (NB) or PML oncogenic domains (POD).…”