Research

Acute myeloid leukaemia (AML) is an aggressive disorder of haematopoietic stem cells (HSCs) and progenitors, which acquire driver mutations to generate treatment-resistant leukaemic stem cells (LSCs). LSCs fuel the over-proliferation of primitive myeloid progenitors, which damage the bone marrow and multiple organs, resulting in widespread tissue devastation. Current AML therapies are toxic to normal haematopoiesis, and often fail to eliminate LSCs. The surviving population of LSCs drives minimal residual disease, ultimately causing fatal disease relapses. Given the sobering survival outcomes, it is critical to identify new therapeutic targets for selective LSC elimination. Our laboratory employs multidisciplinary approaches to identify novel therapeutic targets to eradicate LSCs without perturbing normal HSCs and multilineage haematopoiesis. We focus on the following research areas:

Theme 1: Targeting RNA modifications to eliminate LSCs in AML

The field of chemical RNA modifications (the epitranscriptome) is a promising emerging area of intensive investigations in cancer research. Seminal discoveries by our lab and others have revealed that methylation at the N6 position of adenosines (m⁶A) is an important regulator of LSCs in AML (in collaborations with Prof. Donal O’Carroll in Edinburgh). Our central goal is to therapeutically target the key regulators of m⁶A and other diverse RNA modifications to eradicate LSCs. We aim to harness this knowledge to provide novel treatments for blood malignancies and other cancers.

Theme 2: Targeting hypoxia pathways in normal and malignant haematopoiesis

While normal and malignant haematopoiesis occur in the hypoxic (low in oxygen) bone marrow microenvironment, the impact of hypoxia and hypoxia signalling pathways on normal HSC/progenitor fate decisions and leukaemogenesis remains largely unexplored. Our laboratory (in collaboration with Profs. Sir Peter Ratcliffe and Christopher Schofield in Oxford) has discovered that several hypoxia sensing enzymes play important roles in LSC biology and AML propagation. We aim to inhibit these enzymes to eliminate LSCs in AML.

Considering that LSCs serve as a paradigm for other cancer stem cells, our investigations will have broad ramifications in other blood malignancies and solid tumours.

Major Funding

• 2018-2023- Cancer Research UK (Programme Grant), Targeting RNA metabolism to expand haematopoietic stem cells and eradicate acute myeloid leukaemia, £1,822,455
• 2018-2021- Blood Cancer UK (Project Grant), RNA splicing regulator Jmjd6 as a new tumour suppressor in acute myeloid leukaemia, £250,000
• 2017-2020- Medical Research Council (Project Grant), Therapeutic targeting of HIF prolyl hydroxylases in acute myeloid leukaemia, £480,000
• 2013-2019- Cancer Research UK (Senior Fellowship), Hypoxia signalling pathways in normal and leukaemic stem cell functions, £1,679,467

Recent Publications

Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death Woodley K, Dillingh LS, Giotopoulos G et al. Nature Communications (2023) 14(7)

MYC sensitises cells to apoptosis by driving energetic demand Edwards-Hicks J, Su H, Mangolini M et al. Nature Communications (2022) 13(7)

Author Correction: Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation (Nature Immunology, (2022), 23, 6, (927-939), 10.1038/s41590-022-01216-z) Mirchandani AS, Jenkins SJ, Bain CC et al. Nature Immunology (2022) 23(7) 1394

m⁶A RNA modifications: Key regulators of normal and malignant hematopoiesis Sommerkamp P, Brown JA, Haltalli MLR et al. Experimental Hematology (2022) 111(7) 25-31

Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation Mirchandani AS, Jenkins SJ, Bain CC et al. Nature Immunology (2022) 23(7) 927-939

Intrinsic function of the peptidylarginine deiminase PADI4 is dispensable for normal haematopoiesis Young C, Russell JR, Van De Lagemaat LN et al. Biology Open (2022) 11(7)

A functional screen of RNA binding proteins identifies genes that promote or limit the accumulation of CD138+ plasma cells Turner DJ, Saveliev A, Salerno F et al. eLife (2022) 11(7)

CITED2 coordinates key hematopoietic regulatory pathways to maintain the HSC pool in both steady-state hematopoiesis and transplantation Lawson H, van de Lagemaat LN, Barile M et al. Stem Cell Reports (2021) 16(7) 2784-2797

Elevated 2HG does not cause features of tumorigenesis Adam J, Finch A, Sepulveda C et al. Neuro-Oncology (2021) 23(10) iv1-iv1

NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells Codino A, Turowski T, van de Lagemaat LN et al. iScience (2021) 24(7)

Team

Postdoctoral Researchers
Dr Hannah Lawson, Dr Joana Monteiro De Campos, Dr Christopher Mapperley

PhD Students
Jozef Durko, Andrea Tavosanis, Elise Chloé Cécile Georges, Lydia Wang, Edward Blacker

Laboratory Technician/Manager
Lewis Allen

Biography

Kamil R Kranc is a Chair of Haematology (Full Professor) and the Deputy Lead of Centre for Haemato-Oncology at Barts Cancer Institute. Prof. Kranc completed his medical degree at the Medical University of Silesia, Poland (1994-2000), a DPhil (PhD) in Biochemistry at the University of Oxford (2000-2003) and a postdoctoral training at the MRC Human Immunology Unit in Oxford (2003-2007). He was a Junior Principal Investigator at the MRC Molecular Haematology Unit at Oxford (2007-2010), and a Group Leader at the Paul O’Gorman Leukaemia Research Centre at the University of Glasgow (2010-2013). From 2013 to 2018, he was a Professor of Molecular Haematology at the University of Edinburgh. He joined Barts Cancer Institute as a Chair of Haematology in 2018.