Complex Genomic Alterations in TP53 ‐Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia Involving EPOR / JAK2
T. L. Gindina, S. S. Riumin, I. M. Barkhatov, T. Yu Gracheva, D. S. Bug, E. V. Babenko, E. V. Morozova, N. Yu Tsvetkov, N. N. Mamaev, A. D. KulaginABSTRACT
Background
Myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) harboring TP53 mutations are defined by extreme genomic instability, complex karyotypes (CK), and poor prognosis. While large‐scale chromosomal imbalances are common in CK‐MDS/AML, the synergy between focal amplifications of signaling drivers and the disruption of transcriptional regulators remains poorly elucidated.
Methods
We performed a comprehensive clinical, cytogenetic (GTG‐banding, M‐FISH, M‐Band), and molecular (targeted FISH, NGS) analysis of seven patients with MDS and AML characterized by a recurrent and distinct genomic signature.
Results
All cases exhibited highly complex karyotypes on a TP53 ‐mutated background. We identified high‐level focal amplifications of EPOR (19p13.2) and JAK2 (9p24.1), predominantly manifesting as homogeneously staining regions (HSRs) or complex “sandwich‐like” derivative chromosomes. Notably, these signaling alterations consistently co‐occurred with monoallelic deletions of the TCF3 ( E2A ) tumor suppressor (19p13.3) and copy number gains of the ERG transcription factor (21q22). Detailed structural analysis indicates that TCF3 loss likely arises as a structural consequence of chromosome 19 rearrangements driving EPOR amplification. Based on this data, we propose a conceptual model of leukemogenesis where EPOR/JAK2 co‐amplification potentially drives constitutive JAK2/STAT5 signaling, while concurrent ERG gain and TCF3 haploinsufficiency contribute to maturation delay. TP53 deficiency appears to be the primary permissive factor enabling the stabilization of these massive structural rearrangements.
Conclusions
Our findings outline a recurrent and biologically coherent genomic pattern within the spectrum of TP53 ‐mutated myeloid neoplasms, demonstrating significant phenotypic overlap with erythroid leukemia features in a subset of cases. Given the small cohort size, these findings are hypothesis‐generating. However, this convergence of predicted JAK2/STAT5 pathway hyperactivation and transcriptional disinhibition points to a theoretical therapeutic vulnerability that warrants prospective validation in larger collaborative studies.