The Translocation t(7;12)(q36;p13) in Childhood Acute Myeloid Leukemia
Abstract
The reciprocal translocation t(7;12)(q36;p13) gives rise to acute myeloid
leukemia (AML) in infants and very young children. A fusion transcript
MNX1::ETV6 is sometimes detected and an aberrant expression of MNX1 is
detected in 100% of patients but the mechanism of transformation has
previously not been identified. In earlier studies the frequency and outcome
for t(7;12) AML has varied widely and remain contested leading to most
treatment protocols stratifying t(7;12) to a high-risk group, however, the
NOPHO-DBH-AML-2012 protocol used in Sweden does not. The aims of
this project were to determine the frequency, event-free survival and overall
survival of t(7;12) in childhood AML, and identify molecular mechanisms
involved in the development of AML with t(7;12). In Paper I an iPSC model
of t(7;12) was developed. Using this model, a high ectopic expression of
MNX1 and the long noncoding RNAs MNX1-AS1 and MNX1-AS2 from the
same gene locus was observed. The t(7;12) translocation gave rise to a
differentiation block and the model matched the gene expression signature
from t(7;12) AML patient material. In Paper II a murine model was used.
High expression of MNX1 did induce leukemia, however only in transduced
fetal liver cells and not bone marrow cells and primarily in
immunocompromised recipient mice. In Paper III patient data and patient
material was investigated. AML with t(7;12) was associated with trisomy 19
and with CNS involvement. The expression of fusion transcripts in t(7;12)
AML patients was heterogenous, giving rise to several fusion transcripts
involving ETV6. All t(7;12) AML patients had a high expression of MNX1,
MNX1-AS1 and MNX1-AS2. The frequency of t(7;12) AML was 7% in AML
patients 0-2 years old. Patients with t(7;12) AML often suffers relapse but
allogeneic hematopoietic stem cell transplantation (HSCT) was an effective
treatment.
The work presented in this thesis has led to the conclusions that the t(7;12)
translocation drives high expression of MNX1, that the high expression of
MNX1 is the transforming event and that AML with t(7:12) likely has a fetal
cell of origin. The frequency of t(7;12) AML was relatively low at 7% in
AML patients under 2 years old in this study and patients often relapsed but
allogeneic HSCT was an effective treatment.
Parts of work
I. An induced pluripotent stem cell t(7;12)(q36;p13) acute myeloid leukemia model shows high expression of MNX1 and a block in differentiation of the erythroid and megakaryocytic lineages.
Nilsson T., Waraky A., Östlund A., Li S., Staffas A., Asp J., Fogelstrand L., Abrahamsson J., and Palmqvist L. Int J Cancer, 2022. 151(5): p. 770-782 https://doi.org/10.1002/ijc.34122 II. Aberrant MNX1 expression associated with t(7;12)(q36;p13) pediatric acute myeloid leukemia induces the disease through altering histone methylation.
Waraky A., Östlund A., Nilsson T., Weichenhan D., Lutsik P., Bähr M., Hey J., Adamsson J., Morsy M.H.A., Li S., Fogelstrand L., Plass C., and Palmqvist L. Haematologica, 2024. 109(3): p. 725-739 https://doi.org/10.3324/haematol.2022.282255 III. Characterization of Pediatric Acute Myeloid Leukemia with t(7;12)(q36;p13).
Östlund A., Waraky A., Staffas A., De Moerloose B., Arad-Cohen N., Cheuk D., Fernandez Navarro J.M., Jahnukainen K., Kaspers G.J.L., Kovalova Z., Pasauliene R., Saks K., Zeller B., Norén-Nyström U., Hasle H., Fogelstrand L., Abrahamsson J., and Palmqvist L. Manuscript
Degree
Doctor of Philosophy (Medicine)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Institute of Biomedicine. Department of Laboratory Medicine
Disputation
Fredagen den 26 april 2024, klockan 9.00, sal 2119, Hus 2 Entré F, Hälsovetarbacken, Arvid Wallgrens backe 4, Göteborg
Date of defence
2024-04-26
Date
2024-04-11Author
Östlund, Anders
Keywords
Acute myeloid leukemia
Cancer
Publication type
Doctoral thesis
ISBN
978-91-8069-697-5 (PRINT)
978-91-8069-698-2 (PDF)
Language
eng