Therapy-related adult acute lymphoblastic leukemia with t(4;11)(q21; q23): MLL rearrangement, p53 mutation and multilineage involvement

Abstract

A diagnosis of pro-B acute lymphoblastic leukemia (ALL) with CD15+ was made in a 42-year-old woman, 12 months after the treatment of uterine adenocarcinoma by carboplatinum, anthracyclines, etoposide and radiotherapy. Molecular cytogenetic studies revealed a karyotype with multiple chromosome changes, including the t(4;11)(q21;q23) and a 17p-chromosome, with MLL disruption and 17p13/p53 gene deletion in 86% of the cells. A p53 exon 6 mutation was documented, resulting in p53 protein stabilization, with 20% of the cells reacting with the 1801 anti-p53 monoclonal antibody. Dual-color FISH using MLL and p53 probes was performed on peripheral blood smears, providing direct evidence of the involvement of the blast cells and of the granulocytic lineage. Only a partial, shortlasting response was obtained by induction treatment, confirming that a poor prognosis is associated with therapy-related ALL with the 4;11 translocation.

Therapy‐related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: report on two new cases and review of the literature since 1992

“…This review is based on data from Felix Mitelman's Catalogue on Chromosome Aberrations in Cancer (Mitelman, 1998), our own search of the literature and the two new cases presented. Since 1992 a total of 22 cases of t‐ALL and one case of therapy‐related lymphoblastic lymphoma with balanced chromosome aberrations involving chromosome band 11q23 have been reported (Auxenfants et al , 1992; Kobayashi et al , 1993; Jonveaux et al , 1994; Narayanan et al , 1994; Domer et al , 1995; Felix et al , 1995; Imashuku et al , 1996; Zhang et al , 1996; Megonigal et al , 1997; Nasr et al , 1997; Rowley et al , 1997; Laughlin et al , 1998; Pinto et al , 1998; Secker‐Walker et al , 1998; Bigoni et al , 1999; Thandla et al , 1999) (Table I).…”

Secondary myelodysplastic syndrome in a patient with Philadelphia-positive acute lymphoblastic leukemia after achieving a major molecular response with hyperCVAD plus imatinib mesylate

“…The abnormalities initially were nonspecific, but we eventually detected a clone with the translocation (4;11) and MLL gene rearrangement, findings clearly associated with MDS and acute leukemia. Around 5%-10% of MLL gene associated leukemias (i.e., myeloid or lymphoid leukemia) are therapy related [19][20][21]. We could not determine which drug was responsible for the development of the new chromosomal abnormality in our patient.…”

Biochemistry of the Mixed Lineage Leukemia 1 (MLL1) Protein and Targeted Therapies for Associated Leukemia

“…Recurrent MLL1 translocations account for >70% of infant acute leukemias (both ALL and AML) and are also observed in approximately 10% of de novo AML in adults (Krivtsov and Armstrong, 2007), and in therapy-related leukemias that develop in patients treated with topoisomerase II inhibitors (Bigoni et al, 1999;Felix et al, 1995;Krivtsov and Armstrong, 2007). Chromosomal translocations fuse the N-terminal part (~1400 amino acids) of the MLL1 protein in-frame to one of more than 60 partner proteins that range from nuclear factors to cytoplasmic proteins (Daser and Rabbitts, 2005;Huret et al, 2001;Schoch et al, 2003).…”