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Review
. 2018 Feb;75(3):417-446.
doi: 10.1007/s00018-017-2620-z. Epub 2017 Aug 17.

Molecular processes involved in B cell acute lymphoblastic leukaemia

Camille Malouf  1 , Katrin Ottersbach  2
Affiliations
Review

Molecular processes involved in B cell acute lymphoblastic leukaemia

Camille Malouf et al. Cell Mol Life Sci. 2018 Feb.

Abstract

B cell leukaemia is one of the most frequent malignancies in the paediatric population, but also affects a significant proportion of adults in developed countries. The majority of infant and paediatric cases initiate the process of leukaemogenesis during foetal development (in utero) through the formation of a chromosomal translocation or the acquisition/deletion of genetic material (hyperdiploidy or hypodiploidy, respectively). This first genetic insult is the major determinant for the prognosis and therapeutic outcome of patients. B cell leukaemia in adults displays similar molecular features as its paediatric counterpart. However, since this disease is highly represented in the infant and paediatric population, this review will focus on this demographic group and summarise the biological, clinical and epidemiological knowledge on B cell acute lymphoblastic leukaemia of four well characterised subtypes: t(4;11) MLL-AF4, t(12;21) ETV6-RUNX1, t(1;19) E2A-PBX1 and t(9;22) BCR-ABL1.

Keywords: B cell acute lymphoblastic leukaemia; BCR-ABL1; E2A-PBX1; ETV6-RUNX1; MLL-AF4; Paediatric leukaemia.

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Figures

Fig. 1
Fig. 1
Biology of t(4;11) MLL-AF4 pro-B acute lymphoblastic leukaemia. The MLL-AF4 fusion gene and AF4-MLL reciprocal fusion gene are shown with their main interaction partners. Both induce a deregulated epigenetic signature leading to an upregulation of stem-cell signature genes, positive regulators of cell division and inhibitors of apoptosis. The DOT1L inhibitor (EPZ5676), I-BET inhibitor (I-BET151), p-TEFB inhibitor (flavopiridol), WDR5 inhibitor (MM-401) and LEDGF inhibitor (CP65 small peptide) are potential therapeutic agents that target various members of the MLL-AF4 complex and its regulated genes
Fig. 2
Fig. 2
t(12;21) ETV6-RUNX1 leukaemia pre-B acute lymphoblastic leukaemia. The different parts of the ETV6-RUNX1 fusion gene are depicted and include the repression domains of ETV6 with almost the entire RUNX1 gene. The ETV6-RUNX1 fusion gene can alter gene expression by targeting RUNX1- and ETV6-target genes such as MCSFR and stromelysin-1. This leukaemia requires cooperating genetic mutations including the inactivation of ETV6, IKAROS, PAX5, CDKN2A and overexpression of ASEF. The prognosis is excellent and almost all patients are cured under the current therapy regimens
Fig. 3
Fig. 3
t(1;19) E2A-PBX1 pre-B acute lymphoblastic leukaemia. E2A-PBX1 can interact with GCN5 to increase its stability through acetylation or with HDM2 to initiate its degradation through ubiquitination. E2A-PBX1 can constitutively activate the expression of PBX1- target genes, which are expressed at low levels under physiological conditions. Many biological pathways contribute to t(1;19)+ pre-B ALL including the activation of Notch ligands, mTOR/PI3K/AKT, JAK/STAT, AuroraB kinase and the hyperphosphorylation of PLCγ2 through specific kinases. Potential therapeutic agents that target these pathways are shown in red
Fig. 4
Fig. 4
t(9;22) BCR-ABL1 pre-B acute lymphoblastic leukaemia. This leukaemia depends on the hijack of signalling pathways, including the constitutive activation of ABL kinase and the activation of PI3K/AKT/mTOR pathways. These can be targeted by inhibitors of ABL (imatinib), mutant forms of BCR-ABL1 (asciminib/ABL001 and nilotinib) and PI3K/mTOR (PI-103 and NVP-BEZ235). The activation of RAS, IL7R, C-MYB/BMI-1 and the phosphorylation of JAK2 can also contribute to disease. RAS can be inhibited by lonafarnib, a farnesyl transferase inhibitor, and ruxolitinib can inhibit JAK2 activity
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