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Acute myeloid leukemia

JAK/MAP kinase pathway activation and TP53 mutations in acute leukemia with megakaryocytic and erythroid differentiation

Leukemia volume 32, pages 1842–1845 (2018)Cite this article

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Acute leukemia with megakaryocytic and erythroid differentiation (ALMED) is an exceptionally rare and highly aggressive subtype of acute myeloid leukemia (AML), where the neoplastic blasts express both erythroid and megakaryocytic lineage-associated antigens in addition to exhibiting overlapping morphologic characteristics of proerythroblasts and megakaryoblasts [1,2,3]. Previous studies, including ours, have convincingly demonstrated ALMED phenotype in JAK2 V617F/+/Tp53−/−, NRASG12D/+/Tp53−/−, and ERG transgenic mouse models, suggesting a cooperative role of JAK/MAP kinase pathway activation and TP53 mutations in the pathogenesis of ALMED [4,5,6,7]. However, mechanism of pathogenesis of human ALMED has not been studied. Here, we present direct evidence of similar mechanism in human ALMED.

Next-generation sequencing of all coding regions in 400 genes implicated in hematologic malignancies (MSK IMPACT) was performed on both cases and showed the following abnormalities in case 1: JAK1 V658I (VAF 4%), TP53 Y236C (14%), TYK2 V603M (48%), and TET2 P1012L (52%) point mutations, and ERG and RUNX1 amplification; and case 2: JAK2 V617F (VAF 36%) and TP53 V272M (VAF 75%) point mutations, and TET2 S1838Cfs*2 (VAF 43%) and DNMT3A P627Qfs*24 (VAF 72%) frameshift mutations. The copy number state and CN-LOH of each mutated genes were shown in Supplementary Table 2. From these results, we deduce that both JAK1 and TP53 mutations are present in ~10–15% of the cells in case 1 (the low per cent is probably due to suboptimal aspirate with hemodilution), and both JAK2, TP53 and DNMT3A mutations in 70% of the cells in case 2. Furthermore, these mutations likely occur in the same cells. TYK2 and TET2 mutations are present in nearly all cells.

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Acknowledgements

We thank Janine Pichardo and Jeeyeon Baik for their administrative help. This study was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. WX is supported by a startup fund from Department of Pathology at the Memorial Sloan Kettering Cancer Center.

Author contributions:

WX and DCP conceived the study, performed the experiments, and wrote the paper. RR, YZ, RC, AAJ, MA, and MR performed the experiments. All the authors approved the final version of the manuscript.

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Authors and Affiliations

  1. Hematopathology Diagnostic Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Wenbin Xiao, Achim A. Jungbluth, Mikhail Roshal & David C. Park

  2. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Raajit Rampal

  3. Cytogenetic Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Yanming Zhang & Robert Cimera

  4. Diagnostic Molecular Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Maria Arcila

  5. Department of Pathology, Columbia University Medical Center, New York, NY, USA

    David C. Park

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  1. Wenbin Xiao
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Correspondence to Wenbin Xiao.

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Xiao, W., Rampal, R., Zhang, Y. et al. JAK/MAP kinase pathway activation and TP53 mutations in acute leukemia with megakaryocytic and erythroid differentiation. Leukemia 32, 1842–1845 (2018). https://doi.org/10.1038/s41375-018-0145-6

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