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Dynamic transcriptomic tracking directs the treatment for acute leukemia of ambiguous lineage

ABSTRACT: Acute leukemia of ambiguous lineage (ALAL) is a rare subtype of acute leukemia characterized by the lack of straightforward myeloid or lymphoid lineage commitment. Currently, no treatment guidelines are commonly-accepted for ALAL. Herein, we have established an molecular-guided therapeutic approach to classify ALAL as either possessing an transciptional profile with a tendency towards acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). A three and a half years perspective study saw an ALAL patient failed to respond to the ALL-like treatment recommended in most retrospective studies. However, RNA-seq profiling of this ALAL, together with indepth comparative analysis with AML, ALL and healthy bone marrow samples, demonstrated that the ALAL was transcriptomically more similar to AML, and correspondingly a complete molecular remission (CMR) was achieved with AML-like treatment regimen. Moreover, tracking of transcriptomic profile changes at nine time points throughout the treatment successfully detected tumor relapse seven months earlier than conventional approaches. Under the guidance of this Dynamic Transcriptomic Tracking (DTT) approach, we present a further ALAL patient that reached CMR with an AML-like treatment regimen. DTT maybe beneficial in other leukemias that do not possess recommended treatment guidelines. We propose that DTT is condidered for perspective trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE121169 | GEO | 2023/12/23

REPOSITORIES: GEO

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Project description:Acute myeloid leukemia (AML) is associated with poor prognosis, and there is a strong need to develop new therapeutic strategies to improve treatments. We performed a cytokine screen with 114 recombinant proteins to identify selective negative regulators of primitive murine AML cells relative to normal bone marrow cells. The top candidate identified was interleukin 4 (IL4), as it showed the most selective inhibition of leukemia cell growth. Stimulating leukemia cells ex vivo with IL4 and transplanting the cells into mice resulted in reduced leukemia burden and prolonged survival compared with controls. In contrast, IL4 did not inhibit the function of normal hematopoietic stem and progenitor cells in long-term bone marrow repopulation assays. Moreover, we found that IL4 treatment of leukemia cells induced Stat6 phosphorylation, and that leukemia cells with Stat6 knocked out using CRISPR/Cas9-genetic engineering were partially resistant to IL4 stimulation, revealing Stat6 as a critical mediator of the IL4 effect. To evaluate whether IL4 has in vivo therapeutic efficacy, we expressed IL4 ectopically in leukemia cells in vivo and also injected IL4 into leukemic mice; both strategies resulted in the suppression of the leukemia cell burden and increased survival. Further analysis revealed that IL4 treatment induces apoptosis in the leukemia cells. Importantly, IL4 exposure also inhibited the growth and survival of primary AML patient cells. In summary, these findings demonstrate that IL4 selectively inhibits AML cells in a Stat6-dependent manner, thus revealing IL4 as a candidate therapeutic agent in AML. IL4 (ProSpec, East Brunswick NJ, USA) was resuspended following the provider guidelines and stored in aliquotes at -80 °C. Mouse MLL-AF9 leukemia cells were provided by Dr. Benjamin Ebert (Brigham and Women’s Hospital, Boston MA, USA). The murine leukemia cells were cultured in SFEM (StemCell Tech) supplemented with 1% penicillin/streptomycin at 37 °C with 5% CO2.

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Dynamic transcriptomic tracking directs the treatment for acute leukemia of ambiguous lineage

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