Recurrent Novel P2RY8/IGH Translocations in B-Lymphoblastic Leukemia/Lymphoma.

Translocations involving the immunoglobulin heavy chain (IGH) locus are common abnormalities in B-lymphoblastic leukemia/lymphoma (B-ALL) and multiple myeloma. These rearrangements result in a juxtaposition of IGH enhancers to the vicinity of oncogenes, such as MYC and CRLF2, leading to the upregulation of oncogenes. Here, we identified recurrent novel P2RY8/IGH translocations in three B-ALL patients by transcriptome sequencing. Noncoding exon 1 of P2RY8 was translocated to different sites of the IGH gene, resulting in transcripts of P2RY8/IGHM, P2RY8/IGHV, and P2RY8/IGHD. However, a high expression level of truncated P2RY8 was observed in the patients compared with healthy donors, which might be related to the aggressive clinical course and inferior outcome. In summary, we described recurrent novel P2RY8/IGH translocations with high expression levels of P2RY8, which may contribute to the guidelines for clinical diagnosis and treatment.

FEV Maintains Homing and Expansion by Activating ITGA4 Transcription in Primary and Relapsed AML.

Acute myeloid leukemia (AML) is an aggressive hematological malignancy that recurs in approximately 50% of cases. Elevated homing and uncontrolled expansion are characteristics of AML cells. Here, we identified that Fifth Ewing Variant (FEV) regulates the homing and expansion of AML cells. We found that FEV was re-expressed in 30% of primary AML samples and in almost all relapsed AML samples, and FEV expression levels were significantly higher in relapsed samples compared to primary samples. Interference of FEV expression in AML cell lines delayed leukemic progression and suppressed homing and proliferation. Moreover, FEV directly activated integrin subunit alpha 4 (ITGA4) transcription in a dose-dependent manner. Inhibition of integrin α4 activity with natalizumab (NZM) reduced the migration and colony-forming abilities of blasts and leukemic-initiating cells (LICs) in both primary and relapsed AML. Thus, our study suggested that FEV maintains the homing and expansion of AML cells by activating ITGA4 transcription and that targeting ITGA4 inhibits the colony-forming and migration capacities of blasts and LICs. Thus, these findings suggested that the FEV-ITGA4 axis may be a therapeutic target for both primary and relapsed AML.

The role of EVI1 gene quantification in AML patients with 11q23/MLL rearrangement after allogeneic hematopoietic stem cell transplantation.

It remains unclear about the role of the EVI1 gene in AML patients with 11q23/MLL rearrangement (MLL-r AML) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We analyzed the clinical value of EVI1 gene quantification in 96 MLL-r AML patients. High EVI1 expression was found in 73% (70/96) of MLL-r AML patients, and EVI1-high MLL-r AML patients were characterized by high WBC counts (P = 0.046) and low platelet counts (P < 0.001) and commonly had t(6;11) (P = 0.032). In addition, a significant difference was observed in the SETD2 gene mutation between the EVI1 high and low groups (0% vs. 50%, P < 0.001). EVI1-high MLL-r AML patients had worse 2-year OS (49.8% vs. 79.7%, P = 0.01) and 2-year PFS (40.2% vs. 68.1%, P = 0.014) than EVI1-low patients. In 57 MLL-r AML patients undergoing allo-HSCT, poorer 2-year PFS (48.6% vs. 72.4%, P = 0.039) and higher CIR (33.2% vs. 11.1%, P = 0.035) were observed in the EVI1-high patients. Multivariate analysis revealed that pre-EVI1+ was the sole independent factor of high CIR (P = 0.035, HR = 4.97, 95% CI: 1.12-22.04). EVI1+ at 100 days post allo-HSCT was associated with a significantly higher 2-year CIR (P = 0.017). The quantification of the EVI1 gene could be used as an additional marker for early predicting relapse in allo-HSCT MLL-r AML patients.