17p Deletion in Acute Myeloid Leukemia and Myelodysplastic Syndrome. Analysis of Breakpoints and Deleted Segments by Fluorescence In Situ

Abstract

Recently, we and other groups reported in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) a strong correlation between cytogenetic rearrangements leading to 17p deletion, a typical form of dysgranulopoiesis combining pseudo-Pelger-Huët hypolobulation and small vacuoles in neutrophils, and p53 mutation. To gain further insight into this “17p-syndrome,” we studied 17 cases of AML and MDS with 17p deletion by whole chromosome painting (WCP) and fluorescence in situ hybridization (FISH) with probes spanning the 17p arm, including a p53 gene probe. Cytogenetically, 15 patients had unbalanced translocation between chromosome 17 and another chromosome (chromosome 5 in nine cases and unidentified chromosome -add 17p- in three cases), one patient had monosomy 17, and one had i(17q). All rearrangements appeared to result in 17p deletion. Sixteen patients had additional cytogenetic rearrangements. WCP analysis confirmed the cytogenetic interpretation in all cases and identified one of the cases of add 17p as a t(17;22). WCP also identified chromosome 17 material on a marker or ring chromosome in two cases of t(5;17). FISH analysis with 17p markers made in 16 cases showed no deletion of the 17p markers studied in the last two patients, who had no typical dysgranulopoiesis; p53 mutation analysis in one of them was negative. In the 14 other cases, FISH showed a 17p deletion of variable extent but that always included deletion of the p53 gene. All 14 patients had typical dysgranulopoiesis, and all but one had p53 mutation and/or overexpression. These findings reinforce the morphologic, cytogenetic, and molecular correlation found in the 17p- syndrome and suggest a pathogenetic role for inactivation of tumor suppressor gene(s) located in 17p, especially the p53 gene.

Dic (17;20) (p11;q11) Preceded <I>MLL</I> Gene Amplification in a Patient with <I>de novo</I> Mixed-Lineage Leukemia

“…16 Loss of 17p is frequently associated with complete or partial monosomy of chromosome 5 and a poor prognosis in AML/MDS. [1][2][3] Moreover, a recurring abnormality of dic(5;17) (q11-13;p11) is reported in AML/MDS cases. 17 Therefore, a possible cooperation of p53 gene located at 17p13 and a putative tumor suppressor gene at 5q13 has been proposed.…”

“…Recently, a new clinicopathological entity in acute myeloblastic leukemia (AML)/myelodysplastic syndrome (MDS), 17p-syndrome, has been postulated. 2,3 This new entity is characterized by the strong correlation between unbalanced translocations involving 17p deletion, less often monosomy 17 or i (17p), and typical dysgranulopoiesis combining pseudo-Pelger-Huët hypolobulation and small vacuoles in neutrophils, and p53 mutations. Notably, Soenen et al reported that the deletion of one p53 allele, which is located at 17q13, was found in all cases with 17p-syndrome and point mutation of the non-deleted p53 allele in all but one.…”

“…Notably, Soenen et al reported that the deletion of one p53 allele, which is located at 17q13, was found in all cases with 17p-syndrome and point mutation of the non-deleted p53 allele in all but one. 2 Thus, loss of germ line p53 might play an important role in 17psyndrome.…”

TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Current Guidelines, Therapies, and Future Considerations

“…Roughly 70-80% of the TP53 mutations in de novo AML are missense mutations resulting in amino acid alterations. The majority of the mutations fall between the codons 125 and 300 [7]. Missense mutations result in an extended half-life of the altered proteins when compared to its wild-type shorter-lived equivalent leading to the accumulation of unfolded protein that is evident on immunohistochemistry.…”

Comparison of TP53 mutations screening by functional assay of separated allele in yeast and next-generation sequencing in myelodysplastic syndromes

“…TP53 mutations occur in 5-10% of MDS and AML, especially in cases with complex karyotype, often including 17p deletion (i.e. loss of the wild-type TP53 allele) [5] and in the 5q− syndrome, where they are found in about 20% of the cases [6]. Interestingly, the 5q− syndrome is a model of ribosomopathy, like Blackfan Diamond anemia, with haplo-insufficiency for about 40 genes including RPS14 [7,8] leading to activation of the p53 pathway and p53-induced apoptosis of the erythroid cells.…”