Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations

Abstract

The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety‐eight young adults (range: 21‐60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54‐myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of −5/5q‐ (P < .001) and −17/17p‐ (P < .001), but not −7/7q‐ (P = .370). This “typical” CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia‐free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR‐246 that targeted mutant p53, but resistant to MDM2 antagonist MI‐77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.

A‐kinase interacting protein 1 might serve as a novel biomarker for worse prognosis through the interaction of chemokine (C‐X‐C motif) ligand 1/chemokine (C‐X‐C motif) ligand 2 in acute myeloid leukemia

“…In the study, AKIP1 and CXCL1 were negatively correlated with accumulating EFS and accumulating OS in AML patients. The possible explanations might consist of that (a) based on our previous data, AKIP1 high expression was correlated with unfavorable cytogenetic change (such as: MK occurrence) and poor risk stratification, which indirectly led to poor prognosis . (b) AKIP1 high expression might activate CXCL1/CXCL2 downstream oncogenic signaling pathway (such as: Wnt/β‐catenin signaling), which further promoted the self‐renewal of AML stem cell and enhanced the resistance to the chemotherapy; therefore, patient with AKIP1 high expression had poor survival profiles in a long‐term period.…”

Impact of pretransplant measurable residual disease on the outcome of allogeneic hematopoietic cell transplantation in adult monosomal karyotype AML

“…We also did not have information on mutations in TP53 routinely available, mutations of particular interest for patients with MK AML given the strong association between MK AML and TP53 abnormalities. 35 – 38 Other study limitation to consider include its retrospective nature, the fact that transplant protocol assignments were done in a non-randomized fashion, the relatively short follow-up time for patients transplanted most recently in our cohort, and the relative small number of MK patients, resulting in relatively large confidence intervals for outcome estimates. Moreover, some subset analyses of potential interest, e.g.…”

Molecular Approaches to Treating Pediatric Leukemias

“…Despite being originally considered as undruggable, a small molecule screen nearly 20 years ago identified APR-246 via its ability to induce apoptosis in human tumor cells through restoration of the transactivation function of mutant p53 (76). Since that time, several reports have shown anti-leukemic activity of APR-246 in vitro both in ALL (77) and AML (78, 79). A first-in-human trial in refractory hematologic malignancies concluded that APR-246 could be administered safely and induced p53-dependent biologic effects in tumor cells in vivo (80).…”