MLL gene amplification in acute myeloid leukemia and myelodysplastic syndromes is associated with characteristic clinicopathological findings and TP53 gene mutation

• Published in: Human pathology 2015-01, Vol.46 (1), p.65-73
• Main Authors: Tang, Guilin, MD, PhD, DiNardo, Courtney, MD, Zhang, Liping, MD, Ravandi, Farhad, MD, Khoury, Joseph D., MD, Huh, Yang O., MD, Muzzafar, Tariq, MD, Medeiros, L. Jeffrey, MD, Wang, Sa A., MD, Bueso-Ramos, Carlos E., MD
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Chromosomes, Human; DNA Mutational Analysis; Female; Gene Amplification; Genetic Predisposition to Disease; Histone-Lysine N-Methyltransferase; Humans; Immunophenotyping; In Situ Hybridization, Fluorescence; Karyotyping; Leukemia, Myeloid, Acute - complications; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Leukemia, Myeloid, Acute - therapy; Male; Middle Aged; Mutation; Myelodysplastic Syndromes - complications; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - mortality; Myelodysplastic Syndromes - pathology; Myelodysplastic Syndromes - therapy; Myeloid-Lymphoid Leukemia Protein - genetics; Pathology; Phenotype; Retrospective Studies; Risk Factors; Time Factors; Treatment Failure; Tumor Suppressor Protein p53 - genetics
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2014.09.008

Summary MLL gene rearrangements are well-recognized aberrations in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In contrast, MLL gene amplification in AML/MDS remains poorly characterized. Here, we report a series of 21 patients with myeloid neoplasms associated with MLL gene amplification from 1 institution. This series included 13 men and 8 women, with a median age of 64 years. Eleven patients presented as AML with myelodysplasia-related changes, 6 as therapy-related AML, and 4 as therapy-related MDS. All patients had a highly complex karyotype, including frequent −5/del(5q), −18, and −17/del(17p) abnormalities; 16 patients were hypodiploid. TP53 mutations were detected in all 12 patients tested, and 3 patients showed TP53 mutation before MLL amplification. Morphologically, the leukemic cells frequently showed cytoplasmic vacuoles, bilobed nuclei, and were associated with background dyspoiesis. Immunophenotypically, 15 patients had a myeloid and 4 had myelomonocytic immunophenotype. Laboratory coagulopathies were common; 7 patients developed disseminated intravascular coagulopathy, and 3 died of intracranial bleeding. All patients were refractory to therapy; the median overall survival was 1 month, after MLL gene amplification was detected. We concluded that AML/MDS with MLL gene amplification is likely a subset of therapy-related AML/MDS or AML with myelodysplasia-related changes, associated with distinct clinicopathological features, frequent disseminated intravascular coagulopathy, a highly complex karyotype, TP53 deletion/mutation, and an aggressive clinical course.