Investigation of bone marrow failure in acute myeloid leukaemia through targeted sequencing
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Embargo End Date
2027-03-27
ICR Authors
Authors
Ko Ko, T
Document Type
Thesis or Dissertation
Date
2025-03-27
Date Accepted
Abstract
Our group has shown that CD34-negative AML induces haematopoietic stem cells
(HSCs) into a quiescent state, blocking differentiation. If this holds for all AMLs, all
patients should present with pancytopenia. However, some exhibited bi/unilineage
cytopenia.
This thesis explored two key questions regarding bone marrow failure in AML. First, I
investigated the origin of residual mature cells in CD34+ (n=40) and CD34- AML
(n=12) through genotyping to understand why not all patients present with
pancytopenia. I also enumerated putative EPCR+ (Endothelial Protein C Receptor)
HSCs in 108 AML samples to investigate HSC depletion or preservation.
Two-thirds of neutrophils and half of erythroblasts derived from differentiation of
leukaemic blasts, while some mature cells originated from pre-leukaemic and normal
HSCs. Most patients whose neutrophils shared all mutations with blasts had
preserved neutrophils (>1.8x10^9/l), whereas haemoglobin was not preserved
(>100g/l), regardless of erythroblast origin. Although 70% of megakaryocytes derived
from normal HSCs, only two patients had preserved platelets (>100x10^9/l).
Differences in origin of mature cells may explain uni/bilineage cytopenia in some
patients. We propose a new model of marrow failure for core binding factor (CBF)
AML that neutrophils arise from leukaemic blasts and megakaryocytes from normal
HSCs.
We developed a four-marker flow panel (CD34, CD38, CD33 and CD45RA) to identify
putative HSCs in CD34+ CD45RA+ AML, validated through functional assays and
genotyping. HSC fraction derived cells were free of leukaemia mutations, whereas
those from blasts fraction harboured mutations.
HSC enumeration in AML remission samples showed that patients in complete (CR)
and partial remission (PR) had comparable EPCR+ HSCs to control (lymphoma
staging) marrows, while those in CRi (CR with incomplete count recovery) exhibited
significantly lower numbers. If validated, these findings suggest HSC depletion may
contribute to haematopoietic failure in CRi patients post induction chemotherapy. This
may allow modification of therapy e.g. earlier marrow transplant.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Medicine (RMH)