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. 2020 Oct 13;4(19):4887-4897.
doi: 10.1182/bloodadvances.2020002271.

Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation

Damien Luque Paz  1   2   3   4 , Rébecca Jouanneau-Courville  3   4 , Jérémie Riou  5 , Jean-Christophe Ianotto  4   6 , Françoise Boyer  4   7 , Aurélie Chauveau  4   8   9 , Maxime Renard  1   2   3   4 , Jean-Claude Chomel  4   10 , Emilie Cayssials  4   11 , Maria-Pilar Gallego-Hernanz  4   11 , Cédric Pastoret  4   12 , Anne Murati  13 , Frédéric Courtier  13 , Marie-Christine Rousselet  14 , Isabelle Quintin-Roué  15 , Laurane Cottin  1   2   3   4 , Corentin Orvain  4   7 , Sylvain Thépot  1   4   7 , Jean-Marie Chrétien  16 , Yves Delneste  1 , Norbert Ifrah  1   2   4   7 , Odile Blanchet  1   2   3   4   17 , Mathilde Hunault-Berger  1   2   4   7 , Eric Lippert  4   8   9 , Valérie Ugo  1   2   3   4
Affiliations

Leukemic evolution of polycythemia vera and essential thrombocythemia: genomic profiles predict time to transformation

Damien Luque Paz et al. Blood Adv. .

Erratum in

Abstract

Among myeloproliferative neoplasms, polycythemia vera (PV) and essential thrombocythemia (ET) are the 2 entities associated with the most chronic disease course. Leukemic evolution occurs rarely but has a grim prognosis. The interval between diagnosis and leukemic evolution is highly variable, from a few years to >20 years. We performed a molecular evaluation of 49 leukemic transformations of PV and ET by targeted next-generation sequencing. Using a hierarchical classification, we identified 3 molecular groups associated with a distinct time to leukemic transformation. Short-term transformations were mostly characterized by a complex molecular landscape and mutations in IDH1/2, RUNX1, and U2AF1 genes, whereas long-term transformations were associated with mutations in TP53, NRAS, and BCORL1 genes. Studying paired samples from chronic phase and transformation, we detected some mutations already present during the chronic phase, either with a significant allele burden (short-term transformation) or with a very low allele burden (especially TP53 mutations). However, other mutations were not detected even 1 year before leukemic transformation. Our results suggest that the leukemic transformation of PV and ET may be driven by distinct time-dependent molecular mechanisms.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Genes mutated at the time of leukemic evolution of MPNs. (A) The total number of mutations is represented. Mutations in post-PV AML are in red, and those in post-ET AML are in green. (B) Violin plots of the VAF distribution of genes with more than 6 mutations. IDH1 and IDH2 have been summed for this figure.
Figure 2.
Figure 2.
Classification of post-PV/ET AML according to their mutational landscape. Heat map based on the Euclidean distance, displaying the VAF of additional mutations. Genes are listed on the x-axis, and each row corresponds to a patient. The color scale represents the scaled abundance of each variable and is proportional to the allele burden (darker red represents higher allele burden). Three groups were identified for short-term (blue), long-term (orange), and intermediate (green) transformation.
Figure 3.
Figure 3.
Time to leukemic transformation and the molecular landscape of the 3 groups of patients with post-PV/ET AML. (A) Kaplan-Meier curves for leukemia-free survival of the cohort, divided according to the length of time to leukemic transformation. (B) Circos plots show the molecular complexity of the 3 groups.
Figure 4.
Figure 4.
Leukemia-free survival of patients during the chronic phase according to the presence of additional mutations. Kaplan-Meier curve of leukemia-free survival for patients in the chronic phase (n = 109; 80 patients from the control group and 29 patients evolving to leukemic transformation) after propensity score adjustment according to the presence of at least 1 additional mutation, considering all additional mutations (A) or all additional mutations except in TET2 (B).
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