Tracing the Shared Roots of Lymphoblastic Lymphoma and Leukemia
Authors:   , Kroeze Emma 
Published: October 2024

Lymphoblastic lymphoma (LBL) is a common form of non-Hodgkin lymphoma, divided by immunophenotype into T-cell lymphoblastic lymphoma (T-LBL) and precursor B-cell lymphoblastic lymphoma (BCP-LBL). Survival rates after relapse remain very poor and treatment of LBL with toxic multi-agent chemotherapy causes many short- and long-term side effects, expressing the urgency to identify prognostic parameters as well as improved treatment options. LBL is closely related to acute lymphoblastic leukemias, also divided by into T-cell acute lymphoblastic leukemia (T-ALL) and precursor B-cell acute lymphoblastic leukemia (BCP-ALL). The World Health Organization (WHO) does currently not distinguish between LBL/ALL, as the cell of origin is expected to be the same. An LBL diagnosis is made when ≤25% blasts are present in the bone marrow, and for higher percentages an ALL diagnosis is made. The understanding, and therefore treatment, of ALL has been majorly improved over the last decades, whereas the understanding of LBL stays behind. Pediatric LBL patients have been treated for decades with highly toxic multi-agent chemotherapy, that causes many short- and long-term side effects, and approximately one out of five patients does not survive. The high toxicity of treatment accompanied by substantial morbidity and mortality shows the need for improved stratification and prognostic parameters, as well as additional treatment options. In order to reach this goal, more knowledge about these disease entities is necessary. Therefore, the aim of this thesis was to improve risk stratification and treatment opportunities for future children with LBL globally, by studying both clinical characteristics and molecular genetics. The first part of thesis is focused on pediatric T-LBL. We discovered that a prevalent high-risk subtype of T-LBL exists, based on the presence of NOTCH1 gene fusions (21% of our cohort). 4/6 NOTCH1 fusion patients had a relapse, and these patients were 75% of all relapses in our cohort. All patients with NOTCH1 gene fusions had highly elevated levels of CCL17 (TARC), compared to none of the patients without NOTCH1 gene fusion. TARC can therefore serve as easily applicable blood biomarker for high-risk T-LBL patients. The second part of thesis is focused on pediatric BCP-LBL. We detected mutations based on BCP-ALL candidate genes, but with somewhat different frequencies. Mutations in epigenetic modifiers were more frequent in BCP-LBL, whereas mutations in B-cell developmental genes were more frequent in BCP-ALL. Additionally, we showed that the same subtypes as in BCP-ALL exist, based on aneuploidies, transcription-factor driven and cytokine/kinase driven, with a similar distribution. BCP-LBL patients with high-risk genetics, also had a trend towards a decreased outcome compared to patients with favorable-risk genetics. Incorporation of this information could help improve stratification of BCP-LBL. Overall, this thesis provides a deeper understanding of LBL by performing a comprehensive analysis of patient groups diagnosed with immature T-cell as well as B-cell lymphoblastic lymphoma on both the clinical as well as molecular-genetic levels. The important findings of our studies will contribute to improved risk stratification and treatment opportunities for future children with LBL globally.