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Open research questions in Acute Myeloid Leukemia Research

85 unresolved questions extracted from the limitations and future-work sections of 358 Acute Myeloid Leukemia Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Reactivation of RAS/MAPK signaling, often driven by activating NRAS mutations, is a major mechanism of FLT3i resistance in AML; however, effective strategies to overcome this resistance remain lacking.

    Ribonucleotide Reductase Inhibition Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia · 2026 · DOI

  • Measurable residual disease (MRD) is a key prognostic marker in acute myeloid leukemia (AML), but its significance in patients treated with azacitidine and venetoclax (AZA/VEN) outside clinical trials remains unclear.

    Prognostic impact of measurable residual disease in AML patients treated frontline with azacitidine and venetoclax: results from the French VENAURA registry · 2026 · DOI

  • Although FLT3 inhibitors have improved outcomes in both newly diagnosed and relapsed/refractory AML, durable remission remains limited by adaptive resistance and the persistence of leukemia stem cells.

    Bone marrow niche adaptation, leukemic stem cell persistence, and therapeutic resistance in <i>FLT3</i> -mutated leukemia · 2026 · DOI

  • TP53 is known to repress LINE-1 transcription; however, the consequences of TP53 dysfunction on retrotransposition and transcriptional activity in chronic lymphocytic leukemia (CLL) remain unknown.

    Retrotransposon Activity in Chronic Lymphocytic Leukemia: Associations with RNA Splicing and TP53 Dysfunction · 2026 · DOI

  • Luteoloside, derived from the traditional Chinese medicine Lonicera japonica , demonstrates potent anti‐tumor activity against solid tumors, but its effects and mechanisms in hematologic malignancies like AML remain unclear.

    Luteoloside Inhibits the Progression and Enhances Chemosensitivity to Cytarabine in Acute Myeloid Leukemia via β‐Catenin/c‐Myc Axis · 2026 · DOI

  • However, their effects on the bone marrow (BM) microenvironment, and the extent to which these changes correlate with clinical response, remain poorly understood.

    Azacitidine Response in Myelodysplastic Syndromes is Marked by NK-like CD8 T-Cell Expansion and CXCL12+ Reticular Cell Remodeling · 2026 · DOI

  • Larger multicenter studies with longer follow-up are warranted to confirm these findings and further refine prognostic models, potentially integrating molecular risk with measurable residual disease (MRD) assessment to enhance risk prediction in the venetoclax era [17].

    Comparative prognostic performance of ELN 2022 and ELN 2024 risk classifications in a Turkish cohort of acute myeloid leukemia patients receiving hypomethylating agents and BCL-2 inhibitors · 2026 · DOI

  • The concurrent presence of del(5q) and monosomy 7 at the time of diagnosis in BCR/ABL1-positive CML has not been systematically investigated, and this cytogenetic combination is suspected to be associated with a high-risk genomic profile.

    A rare cytogenetic constellation in chronic myeloid leukemia: concurrent Philadelphia chromosome, del(5q), and monosomy 7 at diagnosis · 2026 · DOI

  • However, the biological and spatial characteristics of the AML bone marrow (BM) microenvironment (BMME) in which MRD cells survive remain largely unexplored; in particular, little is known of the BMME in TP53 mutant (TP53mut) AML.

    Niche-level immune evasion in TP53 mutant AML residual disease revealed by spatial proteomics · 2026 · DOI

  • While no conclusions on treatment efficacy can be drawn from this limited case series, these observations document durable remission despite the active disease at transplant in an ultra-high-risk setting and support further investigation of immune-based transplant strategies in NUP98-rearranged AML.

    Durable remission despite transplantation with active disease in therapy-related NUP98::TOP1-rearranged acute myeloid leukemia · 2026 · DOI

  • 01% during/after consolidation) of fusion transcripts predicts survival, the impact of baseline myeloid mutations on OPR and survival with FLAG remains uncertain.

    Integrated Analysis of Genomics, Molecular Responses, and Outcomes of CBF-AML with FLAG-Based Therapy on a Phase II Trial · 2026 · DOI

  • The prediction of complete remission (CR) and first adverse event (AE) is critical for personalizing pAML treatment; however, interpretable machine learning (ML) models that utilize only routine clinical features for this purpose are lacking.

    Development of an interpretable machine learning model to predict complete remission and first adverse event in pediatric acute myeloid leukemia using routine clinical data · 2026 · DOI

  • Although measurable residual disease (MRD) is increasingly used for risk stratification, optimal FLT3-ITD MRD assessment, the prognostic value of peri-transplant MRD dynamics, and their implications to transplant-related decision-making remain unclear.

    Peri-transplant molecular MRD monitoring by targeted NGS in patients with FLT3-ITD mutated acute myeloid leukemia · 2026 · DOI

  • AML-CK is associated with TP53 mutations and chromosome 5q deletions (del5q); however, the drivers and clonal trajectories of aneuploid evolution in HSPCs remain unknown.

    Chromosome 5q deletion drives evolution of aneuploidy in myeloid neoplasms with complex karyotype · 2026 · DOI

  • infectious 7. Gala, D., Behl, H., Shah, M., & Makaryus, A. N. (2024, February). The role of artificial intelligence in improving patient outcomes and future of healthcare delivery in cardiology: a narrative review of the literature. In Healthcare (Vol. 12, No. 4, p. 481). MDPI. doi: 10.3390/healthcare12040481. 8. Hu, D., & Shilatifard, A. (2016). Epigenetics of hematopoiesis hematological and malignancies. Genes & development, 30(18), 2021- 2041. doi: 10.1101/gad.284109.116. 9. Ntziachristos, P., Abdel-Wahab, O., & Aifantis, I. epigenetic hematological (2016). Emerging dysregulation concepts in of IOASD Journal of Medical and Pharmaceutical Sciences | Published by IOASD Publisher | India | 61 malignancies. Nature 1024. doi: 10.1038/ni.3517. immunology, 17(9), 1016- 10. Cobo, I., Tanaka, T., Glass, C. K., & Yeang, C. (2022). Clonal hematopoiesis driven by DNMT3A in monocyte and and TET2 mutations: role atherosclerotic macrophage in disease. Current cardiovascular hematology, 29(1), doi: 1-7. 10.1097/MOH.0000000000000688. opinion biology and 11. Sato, N., Goyama, S., & Kitamura, T. (2025). ASXL1 mutation-related clonal hematopoiesis and and age-related diseases: molecular of insights. International Hematology, 122(3), 327-340. doi: 10.1007/s12185- 025-04038-5.

    Occult Hematopoietic Malignancies: Pathophysiology, Clinical Presentation, and Prognostic Implications · 2026 · DOI

  • An important limitation of this report is that bone marrow, cytogenetic, and molecular studies obtained at relapse remained pending at the time of manuscript preparation. Because matched germline testing was not performed and relapse molecular profiling remained unavailable at the time of manuscript preparation, the precise significance of the persistent NSD1 variant could not be determined.

    Management of Acute Myeloid Leukemia in a Dialysis-Dependent Patient: A Case Report, Literature Review, and Therapeutic Considerations · 2026 · DOI

  • Reference 69 uses single-cell RNA-seq to reveal AML hierarchies relevant to disease progression, but integration of this transcriptomic data with the spatial localization dynamics between metaphyseal and central marrow regions—and how specific molecular subtypes preferentially localize to distinct niches—has not been performed.

    Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour · 2026 · DOI

  • References 67 and 68 establish that leukemia-initiating cells can reside in CD34− fractions in some AML patients and target self-renewing haematopoietic stem cells in chronic lymphocytic leukemia, yet the spatial localization patterns (metaphyseal versus central marrow) and niche dependencies of these phenotypically-distinct leukaemic stem cell populations remain uncharacterized.

    Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour · 2026 · DOI

  • While reference 66 demonstrates that manipulating niche composition (using Cxcl12fl/fl and Scf fl/fl mice) protects haematopoietic stem cells during infection, the extent to which these niche modifications differentially affect leukaemic stem cell behavior in metaphyseal versus central marrow compartments—and whether this translates to improved chemotherapy sensitivity in AML—remains experimentally unaddressed.

    Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour · 2026 · DOI

  • The study identifies N-cadherin+ vascular niche interactions with leukaemic stem cells (referenced in N-cad-tdTomato experiments), but the specific adhesion mechanisms governing metaphyseal versus central marrow localization and their differential response to N-cadherin-targeted therapy (reference 65: telmisartan/ADH-1 function) have not been systematically compared across AML subtypes.

    Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour · 2026 · DOI

  • Reference 46 reports absence of CXCL12 gradients in bone marrow using 3D tissue-wide digital imaging, yet references 50 and 51 demonstrate therapeutic efficacy of CXCR4 inhibition in AML models. The apparent paradox between lack of detectable CXCL12 gradients and CXCR4-dependent leukaemic stem cell localization to specific marrow regions requires resolution through enhanced spatial resolution imaging or alternative chemokine detection methodologies.

    Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour · 2026 · DOI

  • The study demonstrates CXCL12-independent CXCR4 signaling in MLL-AF9 acute myeloid leukemia (reference 49), but the specific downstream mechanisms beyond JAK/STAT5 pathway activation that mediate leukaemic stem cell behavior in the metaphyseal versus central marrow niches remain uncharacterized. Direct mechanistic investigation of alternative CXCR4 effectors in spatially-distinct bone marrow microenvironments is needed.

    Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour · 2026 · DOI

  • The immunofluorescence microscopy and ChIP assays mentioned for certain conditions were not detailed in the methods excerpt; the specific chromatin-level recruitment dynamics of the Ku80-peptide to the MLL breakpoint cluster region during active DSB formation requires further characterization.

    Discovery of an Endonuclease G-inhibitory Ku80-peptide protecting against leukemogenic rearrangements at the MLL breakpoint cluster · 2026 · DOI

  • While DNA-PKcs inhibition with NU7441 was tested in co-treatment experiments, the mechanistic interplay between Ku80-mediated endogenous DNA repair pathways and endonuclease G inhibition at the MLL breakpoint cluster during NHEJ versus homologous DSB repair remains incompletely characterized.

    Discovery of an Endonuclease G-inhibitory Ku80-peptide protecting against leukemogenic rearrangements at the MLL breakpoint cluster · 2026 · DOI

  • The study used doxorubicin and etoposide as DSB-inducing agents at fixed concentrations (2.0 µM and 0.5-10 µM respectively) but did not systematically evaluate whether the Ku80-peptide's protective effect against MLL rearrangements varies across different topoisomerase II inhibitors or alternative DSB-inducing agents.

    Discovery of an Endonuclease G-inhibitory Ku80-peptide protecting against leukemogenic rearrangements at the MLL breakpoint cluster · 2026 · DOI

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85 open questions have been extracted from the limitations and future-work passages of 358 Acute Myeloid Leukemia Research papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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