Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co‐expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T‐lymphoid/myeloid MPAL (T/My MPAL‐NOS), 42 with Ph+ MPAL, 36 with B‐lymphoid/myeloid MPAL (B/My MPAL‐NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL‐NOS was similar to B/T MPAL‐NOS but differed from Ph+ MPAL and B/My MPAL‐NOS. T/My MPAL‐NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL‐NOS showed higher NOTCH1 mutations. By integrating next‐generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1–G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement‐like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement‐like characteristics. Subsequently, we analyzed single‐cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease‐like and common myeloid progenitor disease‐like signatures, G5 and G6 had high expression of granulocyte‐monocyte progenitor disease‐like and monocyte disease‐like signatures, and G7 and G8 had common lymphoid progenitor disease‐like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.
Background: The ETV6-NTRK3 fusion transcript has been found to recurrently identified in both solid tumors and leukemias. It has attracted a lot of interest for the clinical targeted therapy and genetic features in ETV6-NTRK3 positive solid tumors. While the t(12;15)(p13;q25)/ETV6-NTRK3 is a rare genetic aberration in hematologic malignancies at a low frequency of ≤1%. An accumulation of reported cases would be needed to discuss clinical and cytogenetic characteristics of the important entity. Therefore, it is useful to report every case for clinical implication of prognosis or therapy. Case presentation: We report the case of a previously healthy 30-year-old female, who was diagnosed as acute myeloid leukemia (AML) and presented with chemoresistance and short survival. The patient was treated with four cycles of chemotherapy but failed to achieve remission. Then the patient underwent a salvage haploidentical stem cell transplantation. Unfortunately, she worsened within 1 month and died of the refractory leukemia 35 days after transplantation. ETV6-NTRK3 rearrangement was revealed by RNA sequencing but the chromosomal translocation t(12;15)(p13;q25) was cryptic by conventional karyotype analysis. We review the literature and find that the ETV6-NTRK3 fusion transcript is associated with cryptic karyotype, trisomy 8, aggressive and poor prognosis in hematologic malignancy. The clinical and laboratory characteristics of ETV6-NTRK3 positive hematologic malignancies are different from those of solid tumors. Nevertheless, tropomyosin receptor kinase (TRK) inhibitor has powerful anti-tumor activity in patients with TRK fusion–driven cancers, regardless of the tumor type. Conclusions: We demonstrated that TRK inhibitor larotrectinib is an effective treatment on the primary bone marrow (BM) cells derived from the patient described here with ETV6-NTRK3 positive AML. Our report stresses the importance of screening for ETV6-NTRK3 fusion transcript in newly diagnosed leukemias and clinical treatment of TRK inhibitor in hematologic malignancies.
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