Chemotherapy at the wheel of ALL relapse

In this issue of Blood, Li et al(1) present an extensive in-depth genetic characterization of diagnostic, relapse, and remission samples from a cohort of 103 pediatric patients with acute lymphoblastic leukemia (ALL) treated according to the Shanghai Children's Medical Center ALL-2005 frontline protocol. Together with data obtained from 208 serial bone marrow samples collected during ALL therapy, their work suggests that relapse in a fraction of childhood ALL patients is driven by chemotherapy-induced mutations, which impact therapy response

Targeting cytokine- and therapy-induced PIM1 activation in preclinical models of T-cell acute lymphoblastic leukemia and lymphoma

T-cell acute lymphoblastic leukemia and lymphoma (T-ALL/T-LBL) are aggressive hematological malignancies that are currently treated with high dose chemotherapy. Over the last years, the search towards novel and less toxic therapeutic strategies for T-ALL/T-LBL patients has largely focused on the identification of cell intrinsic properties of the tumor cell. However, non cell autonomous activation of specific oncogenic pathways might also offer opportunities that could be exploited at the therapeutic level. In line with this, we here show that endogenous IL7 can increase the expression of the oncogenic kinase PIM1 in CD127+ T-ALL/T-LBL, thereby rendering these tumor cells sensitive to in vivo PIM inhibition. In addition, using different CD127+ T-ALL/T-LBL xenograft models, we also reveal that residual tumor cells, which remain present after short-term in vivo chemotherapy, display consistent upregulation of PIM1 as compared to bulk non-treated tumor cells. Notably, this effect was transient as increased PIM1 levels were not observed in reestablished disease after abrogation of the initial chemotherapy. Furthermore, we uncover that this phenomenon is, at least in part, mediated by the ability of glucocorticoids to cause transcriptional upregulation of IL7RA in T-ALL/T-LBL PDX cells, ultimately resulting in non-cell autonomous PIM1 upregulation by endogenous IL7. Finally, we confirm in vivo that chemotherapy in combination with a pan-PIM inhibitor can improve leukemia survival in a PDX model of CD127+ T-ALL. Altogether, our work reveals that IL7 and glucocorticoids coordinately drive aberrant activation of PIM1 and suggests that IL7 responsive CD127+ T-ALL and T-LBL patients could benefit from PIM inhibition during induction chemotherapy

Post-transplant lymphoproliferative disorders: From epidemiology to pathogenesis-driven treatment

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Orbital plasmablastic lymphoma

Plasmablastic lymphoma is an unusual and aggressive form of diffuse large B-cell lymphoma, which arises more commonly within the oronasal mucosa. It should be considered as a differential diagnosis for rapidly growing periorbital lesions, particularly in the context of HIV positivity

Molecular pathogenesis of B-cell Post-Transplant Lymphoproliferative Disorder: what do we know so far?

Posttransplant lymphoproliferative disorder (PTLD) is a potentially fatal disease that arises in 2%-10% of solid organ and hematopoietic stem cell transplants and is most frequently of B-cell origin. This very heterogeneous disorder ranges from benign lymphoproliferations to malignant lymphomas, and despite the clear association with Epstein-Barr Virus (EBV) infection, its etiology is still obscure. Although a number of risk factors have been identified (EBV serostatus, graft type, and immunosuppressive regimen), it is currently not possible to predict which transplant patient will eventually develop PTLD. Genetic studies have linked translocations (involving C-MYC, IGH, BCL-2), various copy number variations, DNA mutations (PIM1, PAX5, C-MYC, RhoH/TTF), and polymorphisms in both the host (IFN-gamma, IL-10, TGF-beta, HLA) and the EBV genome to B-cell PTLD development. Furthermore, the tumor microenvironment seems to play an important role in the course of disease representing a local niche that can allow antitumor immune responses even in an immunocompromised host. Taken together, B-cell PTLD pathogenesis is very complex due to the interplay of many different (patient-dependent) factors and requires thorough molecular analysis for the development of novel tailored therapies. This review aims at giving a global overview of the currently known parameters that contribute to the development of B-cell PTLD.status: publishe