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. 2018 Feb;32(2):273-284.
doi: 10.1038/leu.2017.213. Epub 2017 Jul 13.

The MLL recombinome of acute leukemias in 2017

C Meyer  1 , T Burmeister  2 , D Gröger  2 , G Tsaur  3 , L Fechina  3 , A Renneville  4 , R Sutton  5 , N C Venn  5 , M Emerenciano  6 , M S Pombo-de-Oliveira  6 , C Barbieri Blunck  6 , B Almeida Lopes  6 , J Zuna  7 , J Trka  7 , P Ballerini  8 , H Lapillonne  8 , M De Braekeleer  9 , G Cazzaniga  10 , L Corral Abascal  10 , V H J van der Velden  11 , E Delabesse  12 , T S Park  13 , S H Oh  14 , M L M Silva  15 , T Lund-Aho  16 , V Juvonen  17 , A S Moore  18 , O Heidenreich  19 , J Vormoor  20 , E Zerkalenkova  21 , Y Olshanskaya  21 , C Bueno  22   23   24 , P Menendez  22   23   24 , A Teigler-Schlegel  25 , U Zur Stadt  26 , J Lentes  27 , G Göhring  27 , A Kustanovich  28 , O Aleinikova  28 , B W Schäfer  29 , S Kubetzko  29 , H O Madsen  30 , B Gruhn  31 , X Duarte  32 , P Gameiro  33 , E Lippert  34 , A Bidet  34 , J M Cayuela  35 , E Clappier  35 , C N Alonso  36 , C M Zwaan  37 , M M van den Heuvel-Eibrink  37 , S Izraeli  38   39 , L Trakhtenbrot  38   39 , P Archer  40 , J Hancock  40 , A Möricke  41 , J Alten  41 , M Schrappe  41 , M Stanulla  42 , S Strehl  43 , A Attarbaschi  43 , M Dworzak  43 , O A Haas  43 , R Panzer-Grümayer  43 , L Sedék  44 , T Szczepański  45 , A Caye  46 , L Suarez  46 , H Cavé  46 , R Marschalek  1
Affiliations

The MLL recombinome of acute leukemias in 2017

C Meyer et al. Leukemia. 2018 Feb.

Abstract

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Age distribution of investigated patients. The age distribution of all analyzed patients (n=2345) is summarized. Upper part: diagram displaying ALL and AML patients. Age at diagnosis was divided into infants (0–1 year), pediatric (1–18 years) and adult patients (>18 years). The number of ALL, AML and other patients is listed below. We also added the information about therapy-induced leukemia (TIL) patients, the number of complex MLL rearrangements (CL) and specified the ‘non-ALL’ and ‘non-AML’ patients (MLL, MDS, lymphoma and other) in more detail for each age group. The precise number of all patient cases is summarized on the right.
Figure 2
Figure 2
Classification of patients according to age classes and disease type. Top: frequency of most frequent TPGs in the investigated patient cohort of MLL-r acute leukemia patients (n=2345). This patient cohort was divided into ALL (left) and AML patients (right). Gene names are written in black, percentages are indicated as white numbers. Fifty-three patients could not be classified into the ALL or the AML disease types, respectively. Middle: TPG frequencies for the infant, pediatric and adult patient group. Bottom: subdivision of all three age groups into ALL and AML patients. Negative numbers refer again to the number of patients that were neither classified to the ‘ALL’ nor to the ‘AML’ subgroup.
Figure 3
Figure 3
Classification of all yet known fusion partner genes by disease. All TPGs identified were grouped by their diagnosed disease type. Genes have been diagnosed in ALL, t-ALL, t-AML, AML, T-ALL, MLL, bilineal acute leukemia (BAL), MDS, t-MDS, chronic myelogenous leukemia (CML), t-CML, juvenile myelomonocytic leukemia (JMML) and lymphoma. Genes in the intersection belong to two different groups. Bold-marked TPGsb are the most frequent ones.
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