Inhibition of MLLT1 limits growth of MLL-AF4 leukaemias without killing healthy haematopoietic stem cells
Rajhansa, S.; Crump, N. T.; Khoo, H. M.; Bozhilov, Y.; Brennan, P. E.; Fedorov, O.; Adams, C.; Farnie, G.; Milne, T. A.; Wilkinson, A. C.
Show abstract
A major challenge in cancer therapeutics has been the identification of targets that are selectively toxic to cancer cells while displaying limited effects on healthy counterparts. Toxicities related to blood production from haematopoietic stem and progenitor cells (HSPCs) can be particularly problematic and result in patient morbidity and mortality. Within haematological malignancies, therapy response rates and patient survival vary widely between cancer subtypes, with leukaemias driven by the MLL-AF4 fusion protein associated with poor prognosis. MLLT1 has been recently identified as a key potential target in acute myeloid leukaemia. Here we evaluated a panel of leukaemia cell lines and healthy HSPCs for their sensitivity to the MLLT1 inhibitor SGC-iMLLT. We found that SGC-iMLLT strongly inhibited MLL-AF4-driven leukaemia growth in vitro and in vivo. By contrast, SGC-iMLLT did not alter in vitro colony forming potential of human HSPCs or affect long-term in vivo function of mouse HSPCs. These results suggest that SGC-iMLLT may have a promising therapeutic window in the treatment of MLL-AF4-driven leukaemias, and that further clinical development is warranted.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Combining LSD1 and JAK-STAT inhibition targets Down syndrome-associated myeloid leukemia at its core 96%
- Resistance to decitabine and 5-azacytidine emerges from adaptive responses of the pyrimidine metabolism network 96%
- Base edited "universal" donor CAR T cell strategies for acute myeloid leukaemia 95%
Similar papers in this journal
- Monosomy 7/del(7q) Cause Sensitivity to Inhibitors of Nicotinamide Phosphoribosyltransferase in Acute Myeloid Leukemia 96%
- Modeling IKZF1 lesions in B-ALL reveals distinct chemosensitivity patterns and potential therapeutic vulnerabilities 96%
- Resistance mechanism to Notch inhibition and combination therapy in human T cell acute lymphoblastic leukemia 95%
Similar papers in this journal
- BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or Menin inhibitor 95%
- Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms 94%
- A JAK/STAT-Mediated Inflammatory Signaling Cascade Drives Oncogenesis In AF10-Rearranged AML 94%
Similar papers in this journal
- Inducing synthetic lethality for selective targeting of acute myeloid leukemia cells harboring STAG2 mutations 95%
- Quantification of measurable residual disease using duplex sequencing in adults with acute myeloid leukemia 95%
- Genome-wide CRISPR Screens Identify Ferroptosis as a Novel Therapeutic Vulnerability in Acute Lymphoblastic Leukemia 94%
Similar papers in this journal
- Ex Vivo Drug Responses and Molecular Profiles of 597 Pediatric Acute Lymphoblastic Leukemia Patients 95%
- Bone marrow lymphocyte dynamics during chemotherapy in pediatric acute myeloid leukemia 94%
- NOTCH1 fusions in pediatric T-cell lymphoblastic lymphoma: a high-risk subgroup with CCL17 (TARC) levels as diagnostic biomarker 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.