We read with interest the response “The closely related rare and severe acute myeloid leukemias carrying EVI1 or PRDM16 mutations share singular biological features” by Eveillard et al.1 to our recent publication.2 EVI1 and PRDM16 belong to the Prdm family, which is characterized by an N-terminal PR domain with multiple zinc fingers. Prdm family members control gene expression through modification of the chromatin state. It has been shown that EVI1 and PRDM16 have similar functions in normal and malignant hematopoiesis.43 They both cause acute myeloid leukemia (AML), and loss of either leads to severe defects of hematopoietic stem cell (HSC) activity. Here, we would like to clarify similarities and differences of EVI1 and PRDM16 as poor prognosis biomarkers in AML.
Eveillard et al. provide evidence that EVI1- and PRDM16-rearranged AML share many features including micromegakaryocytes, multilineage dysplasia, and low myeloperoxidase (MPO)-expressing blasts. Given the critical role of Evi1 and Prdm16 to maintain HSCs,65 the low expression of MPO probably indicates the undifferentiated stem cell-like properties of these types of leukemia. Eveillard et al. also showed that rearrangements of these genes are associated with inferior survival, and are frequently found in patients with secondary AML. These findings, together with those in previous reports,43 suggest that both EVI1 and PRDM16 are activated by chromosomal rearrangements, confer a poor prognosis presumably by promoting stem cell program in leukemia cells, and are involved in the development of secondary AML. It should be noted, however, that another study found only EVI1-rearrangement is associated with monosomy 7, while PRDM16-rearrangement had no preferential association with other cytogenetic abnormalities.7 Therefore, there may be some mechanistic differences between EVI1- and PRDM16-induced leukemogenesis. In addition, whether high expressions of EVI1 and PRDM16 are independent prognostic factors even in secondary AML remains to be elucidated.
High expressions of EVI1 and PRDM16 are also found in a subgroup of AML patients without translocations of these gene loci. We and others have previously shown that EVI1 is a poor prognostic factor in MLL-rearranged AML.2 PRDM16 was also shown to be a transcriptional target of MLL,8 but interestingly, PRDM16 is not up-regulated in MLL-rearranged AML according to the HemaExplorer9 website (http://servers.binf.ku.dk/hemaexplorer/) (Figure 1). Furthermore, a very recent report showed the mutually exclusive expression of EVI1 and PRDM16 in AMLs without obvious translocation.10 High EVI1 expression was mainly detected in MLL-rearranged AML and megakaryocytic-lineage AML, while high PRDM16 expression was detected in myelocytic-lineage AML and myelomonocytic-lineage AML without MLL-rearrangements. Thus, it appears that PRDM16 is up-regulated through different mechanisms from those for EVI1 in AML patients. Further investigation is necessary to understand how these Prdm factors are activated in specific types of AML, and to elucidate their subtype-specific roles in AML development.
- Marion E, Jacques D, Steven R. The closely related rare and severe acute myeloid leukemias carrying EVI1 or PRDM16 mutations share singular biological features. Haematologica. 2015; xxxGoogle Scholar
- Matsuo H, Kajihara M, Tomizawa D. EVI1 overexpression is a poor prognostic factor in pediatric patients with mixed lineage leukemia-AF9 rearranged acute myeloid leukemia. Haematologica. 2014; 99(11):e225-227. PubMedhttps://doi.org/10.3324/haematol.2014.107128Google Scholar
- Goyama S, Kurokawa M. Evi-1 as a critical regulator of leukemic cells. Int J Hematol. 2010; 91(5):753-757. PubMedhttps://doi.org/10.1007/s12185-010-0618-5Google Scholar
- Morishita K. Leukemogenesis of the EVI1/MEL1 gene family. Int J Hematol. 2007; 85(4):279-286. PubMedhttps://doi.org/10.1532/IJH97.06174Google Scholar
- Goyama S, Yamamoto G, Shimabe M. Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. Cell Stem Cell. 2008; 3(2):207-220. PubMedhttps://doi.org/10.1016/j.stem.2008.06.002Google Scholar
- Aguilo F, Avagyan S, Labar A. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011; 117(19):5057-5066. PubMedhttps://doi.org/10.1182/blood-2010-08-300145Google Scholar
- Duhoux FP, Ameye G, Montano-Almendras CP. PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012; 156(1):76-88. PubMedhttps://doi.org/10.1111/j.1365-2141.2011.08918.xGoogle Scholar
- Artinger EL, Mishra BP, Zaffuto KM. An MLL-dependent network sustains hematopoiesis. Proc Natl Acad Sci USA. 2013; 110(29):12000-12005. PubMedhttps://doi.org/10.1073/pnas.1301278110Google Scholar
- Bagger FO, Rapin N, Theilgaard-Monch K. HemaExplorer: a database of mRNA expression profiles in normal and malignant haematopoiesis. Nucleic Acids Res. 2013; 41(D1):D1034-1039. PubMedhttps://doi.org/10.1093/nar/gks1021Google Scholar
- Jo A, Mitani S, Shiba N. High expression of EVI1 and MEL1 is a compelling poor prognostic marker of pediatric AML. Leukemia. 2015. Google Scholar