Covert preleukemia driven by MLL gene fusion

Jan Zuna; Tatiana Burjanivova; Ester Mejstrikova; Zuzana Zemanova; Katerina Muzikova; Claus Meyer; Sharon W Horsley; Lyndal Kearney; Susan Colman; Hana Ptoszkova; Rolf Marschalek; Ondrej Hrusak; Jan Stary; Mel Greaves; Jan Trka

doi:10.1002/gcc.20622

Covert preleukemia driven by MLL gene fusion

Genes Chromosomes Cancer. 2009 Jan;48(1):98-107. doi: 10.1002/gcc.20622.

Authors

Jan Zuna¹, Tatiana Burjanivova, Ester Mejstrikova, Zuzana Zemanova, Katerina Muzikova, Claus Meyer, Sharon W Horsley, Lyndal Kearney, Susan Colman, Hana Ptoszkova, Rolf Marschalek, Ondrej Hrusak, Jan Stary, Mel Greaves, Jan Trka

Affiliation

¹ Department of Paediatric Haematology and Oncology, Childhood Leukaemia Investigation Prague, Charles University Prague, 2nd Medical School, Czech Republic. jan.zuna@lfmotol.cuni.cz

PMID: 18932267
DOI: 10.1002/gcc.20622

Abstract

Acute leukemia is considered to be a two- or multiple-step process. Although there is a considerable knowledge regarding the character of the "first hit," the nature of the "second hit" remains unanswered in most of the cases including leukemias with MLL gene rearrangement. We demonstrate here a striking sequence of events, which include a covert, protracted preleukemic phase characterized by a dominant MLL/FOXO3A clone with intact myeloid differentiation and the subsequent acquisition of a secondary genetic abnormality, leading to overt lymphoblastic leukemia. Backtracking of the secondary acute lymphoblastic leukemia (sALL) with the MLL rearrangement showed no blasts in the bone marrow (BM) during the protracted preleukemic phase. However, at the same time (more than 1 year before the sALL diagnosis) the MLL/FOXO3A was present in up to 90% of BM cells including myeloid lineage, suggesting that the fusion arose in a multipotent progenitor. To identify potential "second hit" precipitating sALL we compared DNA in preleukemic versus fully leukemic samples. The analysis revealed a 10 Mb gain on 19q13.32 in the sALL, absent in the preleukemic specimen. These data provide insight into the dynamics of leukemogenesis in secondary leukemia with MLL rearrangement.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Chromosomes, Human, Pair 19 / genetics
Cytogenetic Analysis
Female
Forkhead Box Protein O3
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Gene Expression Regulation, Leukemic
Gene Fusion*
Gene Rearrangement
Histone-Lysine N-Methyltransferase
Humans
Leukemia, Promyelocytic, Acute / genetics*
Leukemia, Promyelocytic, Acute / metabolism
Leukemia, Promyelocytic, Acute / pathology
Leukemia, Promyelocytic, Acute / therapy
Myeloid Cells / metabolism
Myeloid-Lymphoid Leukemia Protein / genetics*
Myeloid-Lymphoid Leukemia Protein / metabolism
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Polymorphism, Single Nucleotide
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / therapy
Preleukemia / genetics*

Substances

Biomarkers, Tumor
FOXO3 protein, human
Forkhead Box Protein O3
Forkhead Transcription Factors
KMT2A protein, human
Myeloid-Lymphoid Leukemia Protein
Histone-Lysine N-Methyltransferase