Genomic trajectory in leukemogenesis of myeloproliferative neoplasms: a case report

Background: We report a patient with Essential Thrombocythemia (ET), subsequently diagnosed with concurrent myeloid and lymphoid leukemia. Generally, the molecular mechanisms underlying leukemic transformation of Philadelphia-negative myeloproliferative neoplasms (Ph-MPN) are poorly understood. Risk of transformation to acute myelogenous leukemia (AML) is low; transformation to both AML and acute lymphoblastic leukemia (ALL) is extremely low. Genetic defects, including allele burden, order of mutation acquisition, clonal heterogeneity and epigenetic mechanisms are important contributors to disease acceleration.

Case presentation: A 78-year-old Caucasian female originally treated for stable ET, underwent disease acceleration and transition to myeloid sarcoma and B-cell ALL. Genomic reconstruction based on targeted sequencing revealed the presence of a large del(5q) in all three malignancies and somatic driver mutations: TET2, TP53, SF3B1, and ASXL1 at high allele frequency. We propose that the combination of genetic and molecular abnormalities led to hematopoietic stem cell (HSC) injury and disease progression through sub-clone branching. We hypothesize that ancestral reconstruction of genomic data is a useful tool to uncover subclonal events leading to transformation.

Conclusions: The use of ancestral reconstruction of genomic data sheds light on the unique clinical scenario described in this case report. By determining the mutational profile of tumors at several timepoints and deducing the most parsimonious relationship between them, we propose a reconstruction of their origin. We propose that blast progression originated from subclonal events with malignant potential, which coexisted with but did not originate from JAK2 p.V617F-positive ET. We conclude that the application of genomic reconstruction enhances our understanding of leukemogenesis by identifying the timing of molecular events, potentially leading to better chemotherapy choices as well as the development of new targeted therapies.