Research projects

Comparative analysis of genomic and epigenomic alterations induced by leukemogenic AML1/RUNX1 fusion proteins

The AML1 (RUNX1) transcription factor is a crucial regulator of hematopoiesis. Structural abnormalities of the AML1 gene are frequently found in acute leukemias and myelodysplasias, but only few are recurrent events. The most frequent are t(12;21) in pediatric B-cell acute lymphoblastic leukemia (B-ALL) and t(8;21) in adult acute myeloid leukemia (AML), which encode for the TEL/AML1 and AML1/ETO fusion proteins, respectively. Other recurrent albeit rare rearrangements result in expression of the AML1/MECOM and AML1/PRDM16 fusion proteins, respectively, and are associated with both de novo and therapy-related myeloid neoplasms. AML1 fusion proteins share important features, including the capacity to bind specific consensus sequences through the AML1 DNA-binding domain, to maintain protein-protein interactions through the AML1 moiety, and to function as oncogenic transcription factors by recruiting co-repressor complexes to their target sequences on DNA. There are, however, relevant differences, including the prevalent occurrence in different types of hematopoietic malignancies.

Although acute leukemias caused by TEL/AML1 and AML1/ETO have a favorable prognosis with current therapeutic regimens, there are two important problems that remain unresolved: i) the toxicity of the drugs that are employed is relevant, and ii) the risk of disease relapse. Both these issues are particularly critical in the case of pediatric malignancies and could be addressed by the use of drugs that directly target AML1 fusion protein functions. Many studies have analyzed the mechanism of action of different AML1 fusion proteins, but a parallel and comparative analysis of their functions in a controlled model system is lacking. We are exploiting a controlled experimental model system of murine hematopoietic stem/precursor cells for a comparative study of these four recurrent AML1 fusion proteins with the aim of identifying specific and common functions. We expect that our findings may be extended to other acute leukemias bearing rarer AML1 abnormalities, and could provide a resource for the design of therapeutic regimens that target fusion protein-specific functions.

Drug repurposing for the treatment of acute myeloid leukemia with adverse prognosis

Among adverse-risk AML, a particularly difficult subset is represented by those that carry internal tandem duplications (ITD) in the gene encoding for the receptor tyrosine kinase FLT3, which have a higher relapse rate with current standard therapeutic regimens and, overall, a poorer prognosis. Much effort has been put into the design of kinase inhibitors that target FLT3.; midostaurin was recently introduced as front-line therapy for FLT3-ITD AML, but the selection of additional mutations determining drug resistance is frequent. Such resistance could be circumvented by combination with conventional chemotherapy, an option that is not always applicable to older patients who do not tolerate intensive regimens. In consideration of its frequency and adverse prognosis, the search for additional treatment options in this patient group is urgently needed.

We recently screened a collection of >3,000 compounds that have already been approved by the FDA or are in advanced phase clinical trials for their efficacy in inhibiting the growth of two FLT3-ITD positive cell lines (patient derived MV4-11 and MOLM13 cells) and identified 430 drugs that display a significant anti-proliferative effect on both cell lines. A secondary screening was performed to assess the effect of these drugs on 6 cell lines, with and without FLT3-ITD. On the basis of their mechanism of action, effect on cell viability, and Z-score, we selected 5 drugs for further analyses in vitroand in vivo. In case of favorable results, these drugs will be tested in a clinical setting.

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