Mutations in epigenetic regulators are involved in acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation

Abstract

Although steady improvements to chemotherapeutic treatments has helped cure 80% of childhood acute lymphoblastic leukemia (ALL) cases, chemotherapy has proven to be less effective in treating the majority of adult patients, leaving allogeneic hematopoietic stem cell transplantation (allo-HSCT) as the primary adult treatment option. Nevertheless relapse are the leading cause of death following allo-HSCT. The genetic pathogenesis of relapse following allo-HSCT in Philadelphia chromosome- negative ALL (Ph− ALL) remains unexplored. We performed longitudinal whole-exome sequencing analysis in three adult patients with Ph− B-cell ALL (Ph− B-ALL) on samples collected from diagnosis to relapse after allo-HSCT. Based on these data, we performed target gene sequencing on 23 selected genes in 58 adult patients undergoing allo-HSCT with Ph− B-ALL. Our results revealed a significant enrichment of mutations in epigenetic regulators from relapsed samples, with recurrent somatic mutations in SETD2, CREBBP, KDM6A and NR3C1. The relapsed samples were also enriched in signaling factor mutations, including KRAS, PTPN21, MYC and USP54. Furthermore, we are the first to reveal the clonal evolution patterns during leukemia relapse after allo-HSCT. Cells present in relapsed specimens were genetically related to the diagnosed tumor, these cells therefore arose from either an existing subclone that was not eradicated by allo-HSCT therapy, or from the same progenitor that acquired new mutations. In some cases, however, it is possible that leukemia recurrence following allo-HSCT could result from a secondary malignancy with a distinct set of mutations. We identified novel genetic causes of leukemia relapse after allo-HSCT using the largest generated data set to date from adult patients with Ph− B-ALL.

SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia

“…H3K36me3 is deposited in the bodies of expressed genes 32 due to the interaction of SETD2 with hyperphosphorylated RNA polymerase 2. 7,18 Consistent with this, we found a strong correlation of H3K36me3 level and expression by RNAseq ( Figure 2H); however, H3K36me3 levels plateaued in highly expressed genes. As expected, SETD2-mutant cells had decreased H3K36me3 at all expression levels.…”

“…[1][2][3][4] Despite recent efforts to develop novel therapies, the mainstay of treatment of both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) remains chemotherapy with DNA-damaging agents. We and others have reported an enrichment of mutations in epigenetic regulators in relapsed acute leukemia, [5][6][7] suggesting an association with chemotherapy resistance.…”

Persistent donor derived Vδ4 T cell clones may improve survival for recurrent T cell acute lymphoblastic leukemia after HSCT and DLI

“…This T cell expansion may be enhanced by IL-2 and IFN-γ which were used with DLI [16, 17]. However, even the relapse with the same Vδ5 leukemic clone, whether there was evolution in another molecule that may affect the biological behavior of a leukemic clone remains unclear, this may be identified by deep sequencing of the patient samples, which were collected at each instance of disease recurrence [18–20]. …”

Sequential intensified conditioning followed by prophylactic DLI could reduce relapse of refractory acute leukemia after allo-HSCT

“…Ganciclovir was given for 2 weeks pre-transplantation for prophylaxis of CMV infection, and was administered once again when CMV-emia occurred [4]. Preemptive therapy for EBV-emia was according to our previous description [38, 41].…”

“…Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is commonly perceived as the only curable option for refractory leukemia [1-4]. However, patients with advanced stage who proceed directly to HSCT, especially those with high leukemia burden pre-transplantation, are likely to do poorly [5, 6].…”