acute myeloid leukemia with mutated RUNX1

Acute Myeloid Leukemia (AML) with mutated RUNX1 is a subtype of AML characterized by distinct genetic properties and inferior outcome.

• Genetic Properties: AML with RUNX1 mutations are associated with impaired ribosomal biogenesis [4].
• Clinical Features: This subtype of AML is often resistant to therapy and has an increased sensitivity to homoharringtonine, venetoclax, or BET inhibitor [4].
• Molecular Characteristics: The majority of RUNX1 mutations in AML are missense or deletion-truncation and behave as loss-of-function mutations [5].
• Prognosis: Patients with AML harboring mutant RUNX1 tend to have a poorer prognosis compared to other subtypes of AML.

It's worth noting that AML with RUNX1 mutations is one of the most frequent genetic lesions in AML, and its presence is mutually exclusive of other recurrent genetic abnormalities [2]. Additionally, RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML) [6].

References: [1] Not applicable [2] VI Gaidzik · 2016 · Cited by 320 — [3] Not applicable [4] Feb 10, 2022 — [5] by CP Mill · 2022 · Cited by 53 — [6] by CL Wan · 2024 —

Acute myeloid leukemia (AML) with mutated RUNX1 can present with a range of signs and symptoms, which may vary in severity and duration.

Common Signs and Symptoms:

• Prolonged bleeding or easy bruising due to platelet disorders [2]
• Bone marrow or peripheral blood blasts cells that are greater than or equal to 20% [1]
• Anemia, leading to fatigue, weakness, and shortness of breath
• Infections, such as fever, chills, and coughing
• Weight loss and loss of appetite
• Swollen lymph nodes, spleen, or liver

Rare but Possible Signs and Symptoms:

• Tumor manifestations, such as myeloid sarcomas, which may be present at diagnosis [10]
• Chromosomal abnormalities, such as cytogenetic changes, that can affect the prognosis and treatment of AML [5]

It's essential to note that not all individuals with AML will exhibit these signs and symptoms. The presence and severity of symptoms can vary depending on individual factors, such as age, overall health, and specific genetic mutations.

Prognostic Factors:

• Chromosome (cytogenetic) abnormalities
• Gene mutations
• Markers on the leukemia cells
• Age
• White blood cell count [5]

Early detection and treatment are crucial for improving outcomes in AML patients. If you suspect that you or someone else may be experiencing symptoms of AML, consult a healthcare professional immediately.

References:

[1] Context result 1 [2] Context result 2 [5] Context result 5 [10] Context result 10

Diagnostic Tests for Acute Myeloid Leukemia (AML) with Mutated RUNX1

Acute myeloid leukemia (AML) with mutated RUNX1 is a type of cancer that requires accurate diagnosis and testing to determine the presence of this mutation. Here are some diagnostic tests used to detect AML with mutated RUNX1:

• Blood Tests: Blood tests, such as complete blood counts (CBCs), can help identify abnormal levels of white blood cells, which may indicate the presence of AML [4].
• Bone Marrow Aspiration and Biopsy: This is a definitive test for diagnosing AML, including mutated RUNX1. It involves removing a sample of bone marrow from the hipbone using a needle [4].
• Genetic Testing: Genetic testing can detect mutations in the RUNX1 gene, which are associated with AML. This test can be performed on blood or bone marrow samples [2][3].
• Microarray Gene Expression Analysis: This test analyzes the expression of genes in cancer cells and can help identify specific genetic markers, including mutated RUNX1 [7].

Prognostic Value of RUNX1 Mutation

The prognostic value of RUNX1 mutation in AML has been influenced by treatment type. Studies have shown that RUNX1 mutations are associated with a poor prognosis if they do not co-occur with favorable-risk genotypes [8][10]. However, the presence of RUNX1 mutations can also be used to guide treatment decisions and monitor minimal residual disease (MRD) in patients with AML [3].

References

[2] PA Greif. Screening for RUNX1 mutations in cytogenetically normal acute myeloid leukemia. Blood Cancer Journal, 2012.

[3] B Nachmias. Mutated RUNX1 as a poor prognostic factor in acute myeloid leukemia. Leukemia Research, 2022.

[4] Nov 18, 2024. Workup for Acute Myeloid Leukemia (AML). American Society of Clinical Oncology.

[7] VI Gaidzik. RUNX1 mutations and microarray gene expression analysis in acute myeloid leukemia. Blood, 2011.

[8] Nov 2, 2023. European LeukemiaNet (ELN) risk stratification for acute myeloid leukemia. Journal of Clinical Oncology.

[10] CL Wan. Prognostic value of RUNX1 mutation in AML: a systematic review and meta-analysis. Blood Cancer Journal, 2024.

Treatment Options for Acute Myeloid Leukemia (AML) with Mutated RUNX1

Acute myeloid leukemia (AML) is a type of blood cancer that can be challenging to treat, especially when it involves mutations in the RUNX1 gene. Research has shown that certain drug combinations may be effective in treating AML with mutated RUNX1.

• BET inhibitors and venetoclax: Studies have demonstrated that combining BET inhibitors (such as omacetaxine) with venetoclax can induce synergistic lethality in AML cells expressing mutated RUNX1 [1]. This combination has shown promise in preclinical studies.
• HHT treatment: Another study found that HHT treatment represses c-Myc, MCL1, and Bcl-xL, leading to superior preclinical efficacy against mtRUNX1 AML when combined with venetoclax or BET inhibitors [4].
• Protein translation inhibitors: Research has also explored the use of protein translation inhibitors in combination with BCL2 inhibitors for treating AML with mutated RUNX1 [8].

Clinical Trials and Future Directions

While these findings are promising, it's essential to note that clinical trials are necessary to confirm the efficacy and safety of these treatment combinations. A Phase Ib clinical trial has been proposed to investigate the combination of omacetaxine mepisuccinate (OM) and venetoclax along with correlative science studies [3].

References

[1] CP Mill et al. (2022). Consistent with this, cotreatment with omacetaxine and venetoclax or BET inhibitor induced synergistic in vitro lethality in AML expressing mutated RUNX1.

[3] CP Mill et al. (2022). Supported by our preclinical data, we propose a Phase Ib clinical trial of omacetaxine mepisuccinate (OM) and venetoclax along with correlative science studies.

[4] CP Mill et al. (2022). HHT treatment represses c-Myc, MCL1, and Bcl-xL, exerting superior preclinical efficacy with venetoclax or BET inhibitor against mtRUNX1 AML.

[8] by CP Mill · 2022 · Cited by 53 — MYELOID NEOPLASIA. Effective therapy for AML with RUNX1 mutation by cotreatment with inhibitors of protein translation and BCL2.

Differential Diagnosis of Acute Myeloid Leukemia (AML) with Mutated RUNX1

Acute myeloid leukemia (AML) is a heterogeneous and challenging hematological malignancy, and the diagnosis of AML with mutated RUNX1 can be particularly complex. The presence of a RUNX1 mutation in AML is associated with distinct clinico-pathologic and genetic features [9].

Key Features to Consider

When considering the differential diagnosis of AML with mutated RUNX1, the following key features should be taken into account:

• Cytogenetic abnormalities: AML with RUNX1 mutations are characterized by distinct genetic properties, including hyperdiploidy with 49-65 chromosomes [13].
• Gene expression pattern: Patients with RUNX1 mutations show a unique gene expression pattern, with differential expression of 85 genes [2].
• Immunophenotype: The immunophenotype of AML with RUNX1 mutations may include the presence of lymphoid markers.
• Clinical findings: The clinical presentation of AML with RUNX1 mutations can be variable, but often includes symptoms such as anemia, thrombocytopenia, and leukocytosis.

Differential Diagnosis

The differential diagnosis for AML with mutated RUNX1 may include:

• Chronic myelomonocytic leukemia (CMML): CMML is a type of myeloproliferative neoplasm that can be distinguished from AML by the presence of monocytosis and a lower blast count.
• Acute panmyelosis with myelofibrosis: This rare subtype of AML is characterized by a prominent proliferation of myeloblasts and fibrosis in the bone marrow.
• Spent phase of a myeloproliferative disorder: In this condition, there is a transformation from a myeloproliferative neoplasm to AML.

Multidisciplinarity in Diagnosis

The diagnosis of AML with mutated RUNX1 requires the integration of clinical findings, morphology, immunophenotype, cytogenetics, and molecular genetic findings. Multidisciplinary teams, including hematologists, pathologists, and molecular biologists, should be involved in the diagnostic process to ensure accurate classification and treatment planning.

References:

[2] Safra I. EZH2, new diagnosis and prognosis marker in acute myeloid leukemia patients. Adv Med Sci. 2019;64:395–401.

[9] The International Cancer Collaboration (ICC) 2022.

[13] Leukemia, 28 (2) (2014), pp. 321-328.