Study of germline alterations of transcription factors in acute leukemia
Cyril Broccardo, PhD, DR2 INSERM
Acute leukemia results from a multi-step process. A first molecular event blocks the hematopoietic cells in the early stages of their differentiation and additional genomic alterations prone these immature cells to proliferate without control.
The first event can be acquired (somatic mutation) or inherited (germline mutation).
We have identified by exome sequencing of members of families with high incidence of acute leukemia some familial alterations in 2 transcription factors:
In collaboration with the University Hospital of Lille, we identified the PAX5R38H mutation in a family in which all three children developed B-acute lymphoblastic leukemia (B-ALL) (Duployez, Jamrog et al., Blood 2021). PAX5 is a central factor in the production of functional B cells (Cresson et al., Oncotarget 2018) and often somatically altered in B-ALL (Familiades et al., Leukemia 2009; Coyaud et al., Blood 2010; Jamrog et al., PNAS 2018). We have recently shown that the PAX5R38H mutant loses the functionality of PAX5 blocking B cells at very early stages of differentiation but reacquires properties that may explain leukemic initiation. We also showed that transformation requires alteration of the Ras and Jak/Stat pathways.
Our team identified, in collaboration with the onco-pediatrics department of the Toulouse University Hospital, a mutation of GATA2 in a family in which all three children developed acute myeloid leukemia (AML) or myelodysplasia after the death of one of the two parents from AML (Pasquet et al., Blood 2013, Donadieu et al., Hematologica 2018). GATA2 is a transcription factor crucial for the emergence and maintenance of hematopoietic stem and progenitor cells (HSPCs). We have modelled this mutation in mice and shown that it disrupts the proportions of HSPC subpopulations as well as their functionality (Largeaud et al., SFH Prize 2020). However, additional alterations seem to be essential for leukemic transformation. The modelization of the cooperation between this germline alteration and these somatic alterations is in progress.
- Transcription factors,
- Germline genomic alterations,
- Acute leukemia,
- Oncogenic cooperation
Institut National de la Santé et de la Recherche Médicale (Inserm) ; Université Toulouse 3 / Paul Sabatier ; Région Occitanie Pyrénées – Méditerranée ; Association Cassandra ACCL ; Les 111 des Arts ; Société Française de lutte contre les Cancers et les leucémies de l’Enfant et de l’adolescent (SFCE) ; Association Capucine ; Association Laurette Fugain ; Association CLPGAA (Constance La Petite Guerrière Astronaute l’Association) ; Fondation Leucémie espoir, Ligue Nationale Contre le Cancer (LNCC).