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

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)

The essential reading list for AML: the m⁶A transcripts Kranc KR Blood (2021) 138(7) 6-7

JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells Lawson H, Sepulveda C, van de Lagemaat LN et al. Blood Advances (2021) 5(7) 889-899

The mRNA m6A reader YTHDF2 supresses pro-inflammatory pathways and sustains hematopoietic stem cell function Mapperley C, Van De Lagemaat L, Lawson H et al. Journal of Experimental Medicine 218(1) 20200829-20200829

Hypoxia-inducible factor 1 (HIF-1) is a new therapeutic target in JAK2V617F-positive myeloproliferative neoplasms Baumeister J, Chatain N, Hubrich A et al. Leukemia (2020) 34(7) 1062-1074

Divide and Rule: Mitochondrial Fission Regulates Quiescence in Hematopoietic Stem Cells Luis TC, Lawson H, Kranc KR Cell Stem Cell (2020) 26(7) 299-301

Systemic silencing of Phd2 causes reversible immune regulatory dysfunction Yamamoto A, Hester J, Macklin PS et al. Journal of Clinical Investigation (2019) 129(7) 3640-3656

Gata2 as a Crucial Regulator of Stem Cells in Adult Hematopoiesis and Acute Myeloid Leukemia Menendez-Gonzalez JB, Vukovic M, Abdelfattah A et al. Stem Cell Reports (2019) 13(7) 291-306

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.