Acute myeloid leukaemia: First debate on leukaemia biology

 
Acute myeloid leukemia (AML) is the most common leukaemia in adults representing about 3% of all cancer cases and 25% of all leukemias. The average age at diagnosis is about 68 years, with an estimated 5-year survival rate of around 7% in patients over 65, compared to 45% in younger patients.¹ AML is a genetically heterogeneous clonal disease deriving from a rare bone marrow (BM) leukaemia stem cell (LSC) population with identifiable somatic mutations in 97.3% of all cases.² Regarding its onset, AML may be subdivided into de novo (primary) AML, therapy-related AML (t-AML) and secondary AML (sAML), the latter emerging alongside previous hematologic disorders, such as myeloproliferative neoplasms or myelodysplastic syndromes (MDS) and representing a model for understanding the transition from normal hematopoiesis to AML development.³ Besides age and comorbidities, the genetic profile of leukaemia cells has played and still plays an essential role as a prognostic factor and a key predictive parameter for selecting the type and intensity of induction and post-induction therapy.⁴ However, the molecular characterization of leukaemia cells does not always translate into genetic-targeting clinical actions. Consequently, most patients receive standard-of-care treatments, accounting for most cases of chemotherapy combinations, unchanged since 1973.⁵ In this scenario, despite some crucial advances in the understanding of the biology of AML and the recent approval of novel strategies, such as venetoclax and hypomethylating agent combinations in chemotherapy-ineligible patients⁶, the overall prognosis of AML patients is still poor due to the high rate of relapse, which translates into a small number of long-term survivors. Cell-intrinsic mechanisms of resistance to therapy result in the persistence of LSCs, hampering complete remission and leading to relapse. However, heterogeneous clinical response is observed even within the same molecular subgroup⁷, suggesting that additional factors beyond genetic background are causative of patient outcomes. In that, the contribution of the leukaemic microenvironment (LME) for AML development and maintenance is gaining much and increasing interest.⁸

The LME comprises a complex network of immune and non-immune cells. The immune compartment of LME is mainly composed of T effector (Teff) and regulatory (Treg) cells, NK cells, dendritic cells (DCs), innate lymphoid cells (ILCs), myeloid-derived suppressor cells (MDSCs), macrophages, all potentially contributing to leukaemia cell development, proliferation, and survival.⁹ In AML, aberrant cytokine production and a profound dysregulation of the frequency and function of immune cell subsets have been described. In particular, increased immune-suppressive cell populations, e.g. Tregs and MDSCs, induce a specific milieu that interferes with the anti-leukaemia immune response, favouring immune escape and limiting the response to therapy.¹⁰ In turn, leukaemia cells are known to shape and remodel the immune microenvironment by modulating the expression of immune checkpoint inhibitors on T cells, secreting immune-inhibitory soluble factors and increasing the local and systemic metabolite composition.¹¹

Non-immune cellular elements, i.e., endothelial, stromal, and osteoprogenitor cells, also contribute to the dysregulation of the BM microenvironment and malignancy progression, concomitantly with the accumulation of driver mutations in hematopoietic stem cells (HSCs).¹² Among non-immune BM microenvironment components, mesenchymal stromal cells (MSCs) are well-known regulators of HSC differentiation and BM structural architecture. MSC dysregulation has been considered a crucial step in leukaemogenesis and BM dysfunction.¹³ MSCs support leukaemia cell survival and metabolic requirements and tune the anti-tumour immune response and responsiveness to treatments through different mechanisms, including cell-to-cell contact, exosome production, and secreted factors.¹⁴ In turn, leukemia cells remodel the transcriptome, proteome, and function of MSCs contributing to an immunosuppressive AML cell-protective phenotype.¹⁵ BM vascular architecture and function are also altered in AML with increased permeability, altered perfusion, and release of normal HSCs to the periphery.

Collectively, a compelling body of evidence has provided an extensive characterization of the biological processes occurring in the AML microenvironment. However, a comprehensive understanding of the cellular and functional interactome within LME and between leukaemia cells and LME is far from settled. This knowledge gap may explain why, despite their potential to circumvent some of the cell-intrinsic resistance mechanisms to conventional therapies, immune system-centered therapeutic interventions aimed at harnessing the immune system against AML have led to unsatisfactory and disappointing clinical results.

During EUROLEUK 2023, the first debate was focused on the immunobiology of AML. An outstanding panel of speakers addressed the crucial questions regarding the interactive network operating in the AML microenvironment and pointed out some of the most relevant biological mechanisms underlying the induction of immune tolerance through the generation of highly suppressive T regulatory cells along with the expansion of exhausted and senescent effector T cells. The latter may represent a hallmark of some subtypes of AML, especially those showing adverse molecular and cytogenetic features at diagnosis, tightly interconnected with a wide spectrum of inflammatory modifications that have been reported in the bone marrow of AML patients. In that, a better understanding of the transition from myelodysplastic syndrome to AML from the perspective of an immune tolerogenic microenvironment was discussed as a potential paradigm to be considered for a wider and comprehensive characterisation of the immune landscape of myeloid malignancies. The contribution of somatic leukaemia cell-intrinsic driver mutations in the creation of an immunosuppressed and inflamed leukaemia microenvironment is also emerging as a crucial point, which indicates the need to integrate the genomic profile of clonal cells with the characterisation of the immune microenvironment as part of a novel approach to AML classification and risk-adapted stratification systems. Finally, the lesson from allogeneic hematopoietic stem cells (alloSCT) was part of the debate. A large body of evidence indicates the compelling role of immune activation as part of the successful outcome of alloSCT, but also as a critical mechanism leading to leukaemia evasion from immunological pressure, ultimately leading to relapse. An integrated approach, which combines omics technologies and a functional approach, is revealing the interdependence of clonal and immune cells in transplanted AML patients.

CONFLICT OF INTEREST

The author reports that there are no competing interests to declare.

FUNDING

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ACKNOWLEDGEMENTS

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Posted on 30 April 202412 September 2024