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2017-03-08T18:35:08.000Z

Somatic TP53 mutations can mediate AML and contribute to disease resistance

Mar 8, 2017
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Acute Myeloid Leukemia (AML) has been reported to arise from Pre-Leukemic Stem Cells (pre-LSCs), which are derived from Hematopoietic Stem and Progenitor Cells (HSPCs). Pre-LSCs can survive chemotherapy thus indicating that they play a role in disease recurrence in AML patients. In AML, somatic mutations of TP53 occurs in approximately 20% of patients and are associated with poor survival rates and increased resistance to intensive therapy. More recently, it has been suggested that TP53 mutations may play a role in the early events of AML, hence the rationale of this study.

In a Letter to the Editor of Blood on 3rd March 2017, Ridhimal Lal from the Medical University of Graz, Graz, Austria, and colleagues discussed their study which investigated the effect of somatic TP53 mutations on early events of AML development.

The results of the study were:

  • Granulocyte and B-lymphocyte differentiation occurred in the spleen and Bone Marrow (BM) of NSGS mice engrafted with human TP53 mutated AML cells
  • Patient-specific somatic TP53 mutation was detected by ultradeep sequencing in up to 100% of human engrafted cells including granulocytes, B-lymphocytes and blasts
  • TP53 mutation was detected in purified CD45+/CD3+ cells from AML patients at diagnosis (75%) with a median TP53 Variant Allele Frequency (VAF) of 5% (range, 1.3–20.7)
  • In Colony-Forming Unit Granulocyte Monocyte (CFU-GM) colonies derived from AML patient specimens, TP53 mutation was the initiating event
  • Loss of heterozygosity at TP53 locus occurred in bulk leukemia cells from AML patient samples and not in CFU-GM colonies derived from Lin-CD34+/CD38-/CD99- single cells
  • Median TP53 VAF in BM samples from patients with TP53 mutated AML at diagnosis, Complete Remission (CR), and Relapsed/Refractory (R/R); 67.5% vs 1% vs 45.5%, P = 0.578

In summation, somatically acquired TP53 mutations characterize pre-LSCs, initiate genetic events and are mediators of resistant disease in AML.

The authors concluded by highlighting that their study adds further evidence to “recent claims of TP53 mutated AML as a distinct disease entity”. They further suggested that their study would have implications for the development of targeted treatment approaches for TP53 mutated AML.

  1. Lal R. et al. Somatic TP53mutations characterize preleukemic stem cells in acute myeloid leukemia. Blood. 2017 Mar 3. DOI: 1182/blood-2016-11-751008. [Epub ahead of print].

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