Session Summaries from the ESH-iCMLf 28th Annual John Goldman Conference on CML: Biology and Therapy - Session 1

Scientific Session: Microenvironment

Chair: Richard Van Etten (Irvine)

This session explored how the bone marrow microenvironment shapes CML stem cell persistence, TKI resistance and the balance between leukemic and normal hematopoiesis. Across a keynote and three presentations, speakers highlighted the active role of niche components, including endothelial cells and macrophages, as well as inflammatory and metabolic signalling. Together, the findings suggest that disrupting interactions between CML cells and their protective microenvironment could complement TKI therapy and provide new approaches to targeting persistent leukemic stem cells. 

Our key takeaways from the presentations:

Keynote presentation

Chronic myeloid leukemia and the bone marrow microenvironment
Speaker: Daniela S. Krause (Mainz)

“The microenvironment provides a sanctuary for leukemic stem cells in CML.” - Daniela S. Krause

Key points:

• Protective niche: The bone marrow microenvironment comprises vascular, stromal, immune and extracellular matrix components that interact with CML cells and can protect leukemic stem cells (LSCs) from therapy. 
• Adhesion: Interactions involving CD44 and endothelial E-selectin help retain CML LSCs within protective niches; disrupting E-selectin can mobilise LSCs, increase cell cycling and improve their elimination. 
• Bidirectional signalling: CML actively remodels its own niche, while the altered microenvironment in turn supports leukemia. IL-6, CXCL12, TGF-β and inflammatory signalling are among the pathways implicated in this reciprocal communication.
• Immune environment: Alterations in T cells, NK cells and macrophages contribute to CML biology, with recent spatial analyses indicating local immune exhaustion, vascular disorganisation and leukemia-specific cellular neighbourhoods during progression. 
• Emerging players: Extracellular vesicles and extracellular matrix components add further complexity to niche signalling and represent areas requiring greater investigation.
• Therapeutic opportunity: Modifying the niche can alter LSC behaviour, raising the possibility that targeting the microenvironment alongside CML-directed therapies could help eliminate residual leukemic stem cells. 

Presentation 1

Macrophage engagement of CD44 promotes chronic myeloid leukemia stem cell growth
Speaker: Tiffany Ricketts (Birmingham)

“There are these functionally distinct macrophage populations, and these arise as a consequence of oncogenic signalling and response to the microenvironment.” - Tiffany Ricketts 

Key points:

• Macrophage diversity: Functionally distinct macrophage populations arise in CML and are further reprogrammed by TKI treatment.
• Divergent signalling: CML-associated macrophages produce different signalling outcomes in leukemic stem cells versus normal HSCs, involving NF-κB and SMAD2/3.
• SPP1–CD44: Increased macrophage-derived SPP1 can engage CD44 and promote NF-κB signalling in CML stem cells.
• CD44: CD44 may contribute to loss of quiescence and self-renewal in normal HSCs, potentially driving their depletion in CML.
• TKI reprogramming: TKI treatment alters macrophage signalling, shifting the balance towards maintenance of non-leukemic HSCs and away from LSC support.
• Future mechanisms: Ligand interactions, co-receptor crosstalk and additional downstream mediators may determine the differential effects of CD44 on HSCs and LSCs.

Presentation 2

Presentation 2: 
Bone marrow endothelial progenitor cells drive TKI resistance in CML via SEMA4D-Plexin B1-mediated metabolic reprogramming

Speaker: Shunjie Yu (Beijing)
“Understanding the contact between niche cells and leukemia cells may reveal a tractable resistance mechanism.” - Shunjie Yu

Key points: 

• Resistant niche: Bone marrow endothelial progenitor cells (EPCs) from TKI-resistant patients showed impaired vascular function but increased adhesion to CML cells. 
• Direct contact: Resistant EPCs protected CML cells from TKI-induced apoptosis predominantly through direct cell-to-cell adhesion, rather than soluble factors. 
• SEMA4D–Plexin B1: The studies identified SEMA4D on CML cells and Plexin B1 on EPCs as a key ligand-receptor axis associated with TKI resistance. 
• Metabolic reprogramming: SEMA4D–Plexin B1 signalling enhanced both glycolysis and oxidative phosphorylation, providing CML cells with a metabolic survival advantage. 
• Pyruvate carboxylase: SEMA4D interacted with SUMOylated pyruvate carboxylase (PC) and promoted PC tetramerisation and activity, providing a mechanistic link between niche adhesion and altered CML metabolism. 
• Therapeutic potential: Blocking SEMA4D restored TKI sensitivity in EPC-protected CML cells and enhanced the effect of imatinib in experimental models, identifying the pathway as a potential therapeutic target.

Presentation 3

MyD88 inhibition using a chemical analogue of a parasitic helminth glycoprotein eradicates TKI resistant cells and inflammatory leukaemia stem cells

Speaker: Thanatpornpat Kritalug (Glasgow) 

“Using 11a to inhibit MyD88 targeted both bulk CD34-positive cells as well as primitive leukemic stem cells, which are most resistant to TKIs.” - Thanatpornpat Kritalug

Key points:

• Inflammatory resistance: TNFα/NF-κB signatures were enriched in both TKI-resistant CML cell lines and TKI-persistent leukemic stem cells, linking inflammation with therapeutic persistence. 
• Inflammatory LSCs: Primitive inflammatory LSCs with high TNFα/NF-κB signalling were particularly resistant to TKIs, providing the rationale for targeting this pathway.
• MyD88: The adaptor protein MyD88, upstream of NF-κB, was increased in TKI-resistant cells, identifying a potential point at which inflammatory survival signalling could be interrupted. 
• SMA 11a: The ES-62-based small-molecule analogue (SMA) 11a inhibits MyD88, reducing expansion and increasing apoptosis in both TKI-sensitive and TKI-resistant CML cell lines. 
• Primitive cells: 11a also targeted primary CML CD34+ cells and primitive LSC populations, including the inflammatory stem cells that were most resistant to TKI treatment. 
• Novel strategy: Targeting MyD88/NF-κB signalling could provide a new approach to eliminating TKI-persistent inflammatory LSCs; in vivo studies with 11a are now underway.