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• Journal article
  Sabbattini PMR, Trasanidis N, Taslim J, Whitwell H, Huang Y, Caputo VS, Ng HL, Chaidos A, Fordwor-Hepburn K, Jia Q, Katsarou A, Atta M, Bua M, Ros-Soto J, Roberts I, Feldhahn N, Crump N, Karadimitris Aet al., 2026,

  CXXC1-dependent IRF4 activity promotes myeloma cell fitness and sustains lenalidomide resistance

  , Blood Journal, ISSN: 0006-4971

  Regulation of oncogenic transcriptional programs in multiple myeloma requires the interplay of histone modifications, their writers and readers with lineage-affiliated transcription factors. The transcription factors IKZF1/3, IRF4 and MYC form an aberrant, myeloma-specific regulatory loop that drives myelomagenesis and resistance to immunomodulatory drugs (IMiDs) such as lenalidomide. Chromatin-based mechanisms that regulate these processes remain incompletely understood. Here we investigate the role of CXXC1, a core component of the H3K4 methyltransferase complex COMPASS, in the activity of the IKZF1/3-IRF4-MYC regulatory loop. We find that clinically, high CXXC1 expression is associated with high-risk proliferative, adverse prognosis disease. Consistent with this, CXXC1 is a myeloma dependency and it regulates cellular fitness programs including cell cycle, MYC targets and DNA damage response. High CXXC1 expression in primary myeloma cells is associated with higher chromatin accessibility, while acute depletion of degron-tagged CXXC1 further validates its role in regulating myeloma cell fitness programs and high-risk transcriptional signatures. CXXC1 interacts with and extensively co-binds to chromatin with IRF4 and IKZF3. Notably, in both lenalidomide-sensitive and -resistant myeloma cells, CXXC1 depletion results in loss of IRF4 and IKZF3 chromatin binding and in parallel it 'breaks' the IRF4 transcriptional self-regulatory loop. Thus, CXXC1 and COMPASS emerge as novel therapeutic targets in IMiD-sensitive and -resistant myeloma by regulating the activity of IRF4 and essential myeloma cell fitness programs.

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• Journal article
  Dąbkowska A, Janowska M, Pastorczak A, Domka K, Nowicka Z, Urbanska Z, Zając W, Bugajewski M, Grzybowska J, Pruchniak P, Fidyt K, Fendler W, Taslim J, Crump NT, Ushmorov A, Patkowska E, Firczuk Met al., 2026,

  mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia.

  , Leukemia

  B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is characterized by impaired B-cell maturation and poor prognosis in relapsed/refractory (R/R) cases. While CD20-targeted immunotherapies offer clinical benefit, their efficacy is limited by low and heterogeneous CD20 expression on BCP-ALL cells. In this study, we demonstrate that overexpression of wild-type IKZF1, a tumor suppressor frequently mutated in high-risk BCP-ALL, upregulates CD20 and promotes leukemic B cell maturation. Using a transcriptional mimicry approach, we identified mTORC1 inhibitors as compounds showing similarity to selected IKZF1-induced transcriptional signatures, including convergence on B-cell maturation and induction of CD20 expression both in vitro and in vivo. mTORC1 inhibition enhanced the antitumor efficacy of anti-CD20 monoclonal antibodies and promoted B-lineage antigen expression, while downregulating immature markers. Mechanistically, CD20 upregulation was mediated via the AKT-FOXO1 axis, with AKT phosphorylation being essential for this effect. Importantly, this phenotypic shift was observed in BCP-ALL models with IKZF1 deletions, highlighting the relevance to high-risk disease. Our findings support the use of mTORC1 inhibitors to sensitize BCP-ALL cells to CD20-directed immunotherapies and provide a strong rationale for their clinical evaluation as adjuncts to anti-CD20 immunotherapy in BCP-ALL.

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• Journal article
  Rajhansa S, Crump NT, Khoo HM, Dopico-Fernandez A, Bozhilov Y, Brennan PE, Fedorov O, Adams C, Farnie G, Milne TA, Wilkinson ACet al., 2026,

  Inhibition of MLLT1 Limits Growth of KMT2A::AFF1 Leukemias Without Killing Healthy Hematopoietic Stem Cells.

  , Exp Hematol, Vol: 160

  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 hematopoietic stem and progenitor cells (HSPCs) can be particularly problematic and can result in patient morbidity and mortality. MLLT1 has been identified as a key potential target in acute myeloid leukemia. Here, we evaluated the sensitivity of the MLLT1 inhibitor SGC-iMLLT using a panel of leukemia cell lines and healthy HSPCs. We found that SGC-iMLLT downregulated MLLT1 target genes and strongly inhibited KMT2A::AFF1-driven leukemia 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 KMT2A::AFF1-driven leukemias and that further clinical development is warranted.

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• Journal article
  Lau I-J, Bloye G, Smith AL, Harman JR, Hamley JC, Sharlandjieva V, Denny N, Chahrour C, Li H, Jackson NE, Vyas P, Davies JOJ, Hughes JR, Crump NT, Milne TAet al., 2026,

  MYB activity drives emergent enhancer activation and enhancer-promoter interactions in acute lymphoblastic leukemia.

  , Blood, Vol: 147, Pages: 2865-2878

  Aberrant enhancer usage is a defining feature of oncogenic transcriptional reprogramming. Therapeutic strategies that disrupt enhancer-driven gene regulation may offer new treatment avenues. MYB is a key hematopoietic transcription factor that is frequently dysregulated in a broad range of cancers and plays a critical role in sustaining malignant cell states, including in aggressive leukemia subtypes such as KMT2A-rearranged leukemias. The molecular mechanisms by which it maintains oncogenic transcription remain incompletely understood. Here, we investigate the role of MYB in directing pathological enhancer activity to drive oncogene expression in leukemia. Using high-resolution Micro Capture-C, we show that upon MYB degradation, highly defined enhancer-promoter interactions at MYB binding sites are lost, correlating with the significant downregulation of target gene expression. When anchored to a gene desert region, the Myb transactivation domain (MybTA) is sufficient and necessary for the nucleation of an enhancer-like region. Critically, long-range chromatin interactions are established up to 400 kb away from where MybTA is anchored. This results in the activation of transcription from distal cryptic elements, which is reduced or abolished in the presence of point mutations that disrupt its interaction with the coactivators P300/CBP. All these results indicate that MYB activity alone is sufficient to generate an enhancer, inducing transcription through precise enhancer-promoter cross talk, and identify the MYB-P300/CBP axis as a therapeutically actionable vulnerability in enhancer-driven malignancies.

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• Journal article
  Ng HL, Burt R, Feldhahn N, 2026,

  BCR::ABL1-induced enhancer reprogramming uncovers hypersensitivity of Ph+ B-ALL cells to enhancer-targeting drugs

  , Advanced Science, ISSN: 2198-3844
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