Impaired Overall Survival in Young Patients With Acute Myeloid Leukemia and Variants in Genes Predisposing for Myeloid Malignancies

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Martin Kirschner - , RWTH Aachen University (Autor:in)
  • Benjamin Rolles - , RWTH Aachen University (Autor:in)
  • Martina Crysandt - , RWTH Aachen University (Autor:in)
  • Christoph Röllig - , Medizinische Klinik und Poliklinik I (Autor:in)
  • Friedrich Stölzel - , Medizinische Klinik und Poliklinik I (Autor:in)
  • Michael Kramer - , Klinik und Poliklinik für Kinder- und Jugendmedizin (Autor:in)
  • Martin Bornhäuser - , Medizinische Klinik und Poliklinik I (Autor:in)
  • Hubert Serve - , Johann Wolfgang Goethe-Universität Frankfurt am Main (Autor:in)
  • Uwe Platzbecker - , Herzzentrum Leipzig (Autor:in)
  • Carsten Müller-Tidow - , Nationales Zentrum für Tumorerkrankungen (NCT) Heidelberg (Autor:in)
  • Kim Kricheldorf - , RWTH Aachen University (Autor:in)
  • Margherita Vieri - , RWTH Aachen University (Autor:in)
  • Matthias Begemann - , RWTH Aachen University (Autor:in)
  • Angela Maurer - , RWTH Aachen University (Autor:in)
  • Marcin W Wlodarski - , Evangelische Hochschule Freiburg (Autor:in)
  • Sushree S Sahoo - , St. Jude Children Research Hospital (Autor:in)
  • Tim H Brümmendorf - , RWTH Aachen University (Autor:in)
  • Edgar Jost - , RWTH Aachen University (Autor:in)
  • Fabian Beier - , RWTH Aachen University (Autor:in)

Abstract

Acute myeloid leukemia (AML) is an aggressive myeloid neoplasm with a relevant subgroup evolving from inherited disorders. According to the WHO 2016 classification, the latter group is categorized as “Myeloid neoplasms with germ line predisposition (MNGLP),”1 comprising various syndromes based on germline mutations in genes such as CEBPA, GATA2, RUNX1, or SAMD92 as well as bone marrow failure syndromes such as telomere biology disorders (TBD).1 The increased risk of AML development at younger age is one common criteria of this category.2

Our study focused on the incidence of TBD as a subcohort of MNGLP in younger AML patients with aberrant karyotype. TBD patients are at particularly high risk of malignant transformation both toward solid tumors and hematologic neoplasms, with the risk of MDS and AML development increased up to 2700- and 200-fold, respectively.3 The identification of classical TBD such as dyskeratosis congenita (DKC) is based on family history and the typical clinical triad (leukoplakia, nail dystrophia, abnormal skin coloring) mostly predominant in younger patients. Due to a less specific and more heterogeneous spectrum of phenotypes in adult-onset TBD, classical DKC signs are often missing and consequently, accurate diagnosis can be challenging. This together with an overall limited awareness of late-onset genetic disorders with first manifestation in adult age results in significant underdiagnosis.4 As a result, adult AML may often be the first manifestation of TBD in selected cases.2,5

TBDs are characterized by impaired telomere maintenance eventually leading to accelerated and functionally critical telomere shortening which in return is associated with chromosomal instability.3 Therefore, AML development in TBD is supposed to be driven mostly by chromosomal aberrations resulting from telomere-mediated chromosomal fusion events or aneuploidy.6 In line with this model, AML arising from TBD is supposed to go along with an increased frequency of aberrant karyotypes probably predominantly involving chromosome arms with short telomeres.4 While the risk of AML development in TBD is known, the reverse incidence of an underlying TBD in adult patients with AML is unclear to date.3

Based on these considerations, the present study aimed to determine the incidence of underlying TBD cases in young newly diagnosed AML patients with aberrant karyotype. Telomere length (TL) screening via PCR in nonclonal cells was performed in remission samples following induction therapy to investigate the relationship between the degree of preexistent telomere shortening and onset of AML. In order not to miss other additional MNGLP, we performed a comprehensive genetic screening for non-TBD-MNGLP in this preselected cohort.

The database of the German Study Alliance Leukemia (SAL) registry including 5207 patients with AML was screened for patients below 35 years (n = 577) fulfilling the following criteria: (1) blast-free state/remission after chemotherapy, (2) aberrant karyotype (≥3 aberrations) detected in diagnostic karyotype or FISH analysis, and (3) available samples of peripheral blood or bone marrow (Figure 1A). Detailed methods are described in the Suppl. section.

Details

OriginalspracheEnglisch
Aufsatznummere787
FachzeitschriftHemaSphere
Jahrgang6
Ausgabenummer11
PublikationsstatusVeröffentlicht - Nov. 2022
Peer-Review-StatusJa

Externe IDs

PubMedCentral PMC9561384
Scopus 85158892158

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