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An integrative multiparametric approach stratifies distinct phenotypes of blast phase chronic myelomonocytic leukemia with differential maturation status and drug sensitivity profiles

ABSTRACT: Approximately 30% of chronic myelomonocytic leukemia patients undergo transformation to a chemo-refractory blastic phase (BP-CMML). Seeking novel therapeutic approaches we profiled blast transcriptomes from 42 BP-CMMLs, observing extensive transcriptional heterogeneity and poor alignment to current AML classifications. BP-CMMLs displayed distinctive transcriptomic profiles, including enrichment for quiescence and variability in drug response signatures. Integrating clinical, immunophenotype and transcriptome parameters, RandomForest unsupervised clustering distinguished immature and mature subtypes characterized by differential expression of transcriptional modules, oncogenes, apoptotic regulators and patterns of surface marker expression. Subtypes differed in predicted response to AML drugs, validated ex vivo in primary samples. Iteratively refined stratification resolved a classification structure comprising five subtypes along a maturation spectrum, predictive of response to novel agents including consistent patterns for RTK, CDK, MTOR and MAPK inhibitors. Finally, we generated a clinically-applicable decision tree to stratify BP-CMML with high specificity and sensitivity, and potentially guide personalized drug selection for improved outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE251806 | GEO | 2024/12/20

REPOSITORIES: GEO

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Project description:Objectives: Platelet derived growth factor receptor alpha (PDGFRα), which, encodes cell surface tyrosine kinase receptors for the platelet derived growth factor family undergoes different types of rearrangements creating fusion genes in myeloid neoplasms. A cryptic deletion at 4q12 creating a fusion gene FIP1L1/ PDGFRα is the most frequent change and is associated with malignant hypereosinophilia that can lead to organ damage. The other infrequent, but consistent change involving PDGFRα seen in acute myeloid leukemia (AML) and in other myeloproliferative neoplasms with eosinophilia is a t(4;12)(q12;p13) that creates a fusion gene with ETV6. This change activates ETV6 via the tyrosine kinase domain of the PDGFRα. In this report we cytogenetically characterized a new t(4;12;6) translocation which developed during transformation to AML in a patient with chronic myelomonocytic leukemia (CMML). Methods: The patient, a 70 year old male diagnosed with CMML; leukemic cells were JAK2- and ABL1/BCR/ABL1 negative and the karyotype was normal. Eight months from diagnosis the disease progressed to AML and concurrently had a low-grade follicular lymphoma. Standard G-band karyotype analysis and FISH analysis was performed to characterize the translocation to develop appropriate therapy based on genetic findings. Results: The patient was initially treated with hydroxyurea and allopurinoal, later it was changed to Azacytidine for CMML. At the time of transformation to AML, the BM karyotype showed a t(4;12;6)( q12;p13;p21.3). FISH with a tricolor 4q12 probe and ETV6 showed fusion between PDGFRα and ETV6.Concurentllty the patient had a low-grade non-Hodgkin lymphoma. Therefore the treatment was changed to imatinib for AML and high dose methylprednisolone and rituximab for lymphoma. Due to continued progression of the disease treatment was changed again to 5+2 (cytarabine 100mg/m2/day) for 5 days and idarubicin (13mg/m2/day for 2 days). Disease progressed further and the patient expired 11 months from diagnosis. Conclusion: This is the first report of development of a variant t(4;12;6) and fusion PDGFRα/ETV6 fusion that developed during transition from CMML to AML. Despite PDGFRα/ETV6 fusion the patient did not respond to imatinib.

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An integrative multiparametric approach stratifies distinct phenotypes of blast phase chronic myelomonocytic leukemia with differential maturation status and drug sensitivity profiles

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