Immature Immunoglobulin Gene Rearrangements Are Recurrent in B Precursor Adult Acute Lymphoblastic Leukemia Carrying TP53 Molecular Alterations.

Renato Bassan,Ursula Giussani,Manuela Tosi,Barbara Peruta,Roberta Cavagna,Orietta Spinelli,Anna Salvi,Greta Ubiali,Alessandro Rambaldi,Tamara Intermesoli,Marie Lorena Guinea Montalvo,Elena Oldani,Chiara Pavoni,Silvia Salmoiraghi

doi:10.3390/genes11090960

Abstract

Here, we describe the immunoglobulin and T cell receptor (Ig/TCR) molecular rearrangements identified as a leukemic clone hallmark for minimal residual disease assessment in relation to TP53 mutational status in 171 Ph-negative Acute Lymphoblastic Leukemia (ALL) adult patients at diagnosis. The presence of a TP53 alterations, which represents a marker of poor prognosis, was strictly correlated with an immature DH/JH rearrangement of the immunoglobulin receptor (p < 0.0001). Furthermore, TP53-mutated patients were classified as pro-B ALL more frequently than their wild-type counterpart (46% vs. 25%, p = 0.05). Although the reasons for the co-presence of immature Ig rearrangements and TP53 mutation need to be clarified, this can suggest that the alteration in TP53 is acquired at an early stage of B-cell maturation or even at the level of pre-leukemic transformation.

Highlights

Rearrangements of immunoglobulin (Ig) and T-cell receptors (TCR) genes are physiologic mechanisms starting in the early stage of lymphopoiesis and following a hierarchical order in which the DH-JH Ig rearrangement is one of the earliest events
We previously demonstrated that these molecular aberrations were associated with the presence of one copy of TP53 gene and increasing age
All patients carrying a TP53 alteration reached complete remission (CR) after induction therapy but out of relapsed in a short time, showing that the relapse rate was significantly higher in TP53 mutated than in wild-type subjects

Summary

Introduction

Rearrangements of immunoglobulin (Ig) and T-cell receptors (TCR) genes are physiologic mechanisms starting in the early stage of lymphopoiesis and following a hierarchical order in which the DH-JH Ig rearrangement is one of the earliest events. Genes 2020, 11, 960 of each distinct lymphoid cell and its descendants, making this peculiar characteristic a suitable marker of clonality when cellular regulatory mechanisms fail. The identification of clonal Ig and TCR rearrangements found clinical application in Minimal Residual Disease (MRD) detection, in. [3] Nowadays, it is established that MRD evaluation represents the most important factor for predicting clinical outcome for ALL patients [4,5,6]. The aberrations involving TP53 gene are detectable in about 10% of adult ALL patients at diagnosis and represent a marker of poor prognosis [8,9,10]. Since the use of intensified treatments could potentially overcome the dismal outcome usually reported in these patients [11], the identification of TP53 mutations at diagnosis is mandatory

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