B acute lymphoblastic leukemia with DUX4 rearrangement

B Acute Lymphoblastic Leukemia (ALL) with DUX4 Rearrangement: A Rare but Distinct Subtype

B-ALL is a type of blood cancer that affects the white blood cells, specifically the B-cells. Within this category, there exists a rare and distinct subtype known as DUX4-rearranged B-ALL.

Characteristics and Prognosis

• DUX4-rearranged B-ALL accounts for approximately 5-7% of all B-ALL cases [5].
• This subtype is characterized by the presence of a specific genetic rearrangement involving the DUX4 gene [2, 3, 8].
• Studies have shown that patients with DUX4-rearranged B-ALL tend to have a good prognosis compared to other subtypes of B-ALL [1, 8].

Genetic Alterations and Associations

• In about 30% of cases, IKZF1 alterations are associated with DUX4-rearrangement without affecting the overall prognosis [1].
• The co-expression of CD2 and CD371 is strongly associated with DUX4 rearrangement in B-ALL patients [4].

Research and Findings

• Recent studies have advanced our understanding of the genetic landscape of B-ALL, including the identification of new subtypes like DUX4-rearranged B-ALL [3].
• Research has also shed light on the mechanisms underlying this subtype, such as the upregulation and binding of DUX4 to the ERG locus [6].

References

[1] Schinnerl et al. (2024) Comprehensive integrative genomic characterization has advanced the classification of B-cell acute lymphoblastic leukemia (B-ALL).

[2] Rehn et al. (2020) DUX4-rearrangement is a recently discovered recurrent genomic lesion reported in 4–7% of childhood B cell acute lymphoblastic leukaemia.

[3] Schinnerl et al. (2019) The recently discovered IGH-DUX4 or, less commonly, ERG-DUX4 rearranged subtype of B-ALL accounts for 5-7% of the cases and is characterized by specific genetic features.

[4] von Stackelberg et al. (2016) Mechanism:DUX4 upregulation and binding at the ERG locus promotes expression of an alternative ERG transcript.

[5] Lilljebjörn et al. (2017) Genetic rearrangements associated with new BCP-ALL subtypes.

[6] Li et al. (2021) Among the recently described subtypes in childhood B-lymphoblastic leukemia (B-ALL) were DUX4- and PAX5-altered (PAX5alt).

[7] Lam WK, Co-expression of CD2 and CD371 in B-ALL is strongly associated with DUX4 rearrangement.

[8] Apr 24, 2023 — DUX4-rearranged B-ALL is an oncogenic subgroup with good prognosis. In 30% of cases, IKZF1 alterations are associated with DUX4-rearrangement without affecting the overall prognosis.

Common Signs and Symptoms

B acute lymphoblastic leukemia (ALL) with DUX4 rearrangement can present with a range of symptoms, including:

• Weakness [2]
• Headaches [7]
• Fever episodes [2]
• Anemia (low red blood cell count) [2]

These symptoms are often nonspecific and can be similar to those experienced by individuals without leukemia. A complete blood count (CBC) is typically performed to confirm the presence of anemia.

Immunophenotype

Individuals with DUX4-rearranged B-ALL may exhibit a distinctive immunophenotype, characterized by:

• CD2± expression
• CD371+ expression [8]

These markers can aid in the diagnosis and identification of this specific subtype of leukemia.

Gene Expression Profile

DUX4-rearranged B-ALL has a unique gene expression profile, which includes the expression of truncated DUX4 isoforms. This genetic alteration is a result of the IGH::DUX4 fusion [1].

References:

[1] DUX4 leukemia is generally characterized by IGH::DUX4 fusions resulting in the expression of truncated DUX4 isoforms and a distinctive gene expression profile.

[2] An 11-year-old girl presented with a 1-month history of weakness, headaches, and fever episodes. Complete blood count showed anemia (hemoglobin, ...).

[7] An 11-year-old girl presented with a 1-month history of weakness, headaches, and fever episodes.

[8] DUX4-rearranged B-ALL has a distinctive gene expression profile and immunophenotype (CD2±, CD371+), and despite the deletion of IKZF1 (...).

Diagnostic Tests for DUX4 Rearranged B Acute Lymphoblastic Leukemia (B-ALL)

DUX4-rearranged B-ALL is a subtype of B-ALL that requires specific diagnostic tests for accurate identification. Here are the key diagnostic tests used to diagnose this condition:

• Gene Expression Profiling: This test involves analyzing the genetic material of the leukemia cells to identify the presence of DUX4 rearrangements [5].
• Next-Generation Sequencing (NGS): NGS is a powerful tool that can detect all types of DUX4 rearrangements, providing resolution on the structure of both the rearrangement and partner genes [2, 8].
• Multiplex-Ligation–Dependent Probe Amplification (MLPA): MLPA is a technique used to analyze leukemic cells collected at diagnosis to identify DUX4 rearrangements [10].
• Cytogenetic Analysis: This test involves examining the chromosomes of leukemia cells to detect any abnormalities, including those associated with DUX4 rearrangements [7].

Key Points

• A reliable identification of DUX4 leukemia currently requires gene expression profiling or next-generation sequencing approaches [5].
• The implementation of Whole Genome Sequencing (WGS) enables the detection of all DUX4 rearrangements and provides resolution on the structure of both the rearrangement and partner genes [2, 8].
• Diagnosis of DUX4-rearranged B-ALL requires genetic testing, which can be challenging due to the complexity of the genetic alterations involved.

References

[1] by JA Rehn · 2020 · Cited by 22 [2] The implementation of WGS enables the detection of all DUX4 rearrangements and provides resolution on the structure of both the rearrangement and partner genes. [3] Jan 5, 2023 — DUX4-rearranged B-ALL is an oncogenic subgroup with good prognosis. In 30% of cases, IKZF1 alterations are associated, without affecting the ... [4] by D Schinnerl · 2024 — Several studies have shown that DUX4 confers a good prognosis, however, most patients have been treated with non-standard or high-risk protocols ... [5] by D Schinnerl · 2019 · Cited by 51 — However, a reliable identification of DUX4 leukemia currently requires gene expression profiling or next-generation sequencing approaches,64 ... [6] by SL Ryan · 2023 · Cited by 50 — Our novel bioinformatic pipeline improved detection of DUX4 rearrangements (DUX4-r): a good-risk B-ALL subtype with high survival rates. Overall ... [7] by R Kansal · 2023 · Cited by 1 — Diagnosis requires genetic testing. Cytogenetic analysis in B-ALL with iAMP21 shows a grossly abnormal chromosome 21 in a karyotype. [8] by D Leongamornlert · 2023 · Cited by 13 — The implementation of WGS enables the detection of all DUX4 rearrangements and provides resolution on the structure of both the rearrangement ... [9] by H Lilljebjörn · 2017 · Cited by 104 — We and others recently discovered that DUX4 rearrangements identify a distinct subtype of adult and pediatric BCP-ALL,22-25 accounting for 4% to 5% of the ... [10] by Z Li · 2021 · Cited by 37 — We used RNA-sequencing (RNA-seq) and multiplex-ligation– dependent probe amplification (MLPA) to analyze leukemic cells collected at diagnosis ...

Treatment Options for B Acute Lymphoblastic Leukemia (ALL) with DUX4 Rearrangement

B ALL with DUX4 rearrangement is a rare and aggressive subtype of the disease. While there are no specific treatment guidelines for this subtype, various studies have investigated the effectiveness of different therapies.

• Standard Treatment Options: The standard treatment options for newly diagnosed childhood acute lymphoblastic leukemia (ALL) include chemotherapy, remission induction therapy, and consolidation therapy [3]. However, these treatments may not be effective in patients with DUX4 rearrangement.
• DUX4 Prognosis: Several studies have shown that DUX4 confers a good prognosis in B ALL, but most patients have been treated with non-standard or high-risk protocols [4].
• Remission-Induction Therapy: Remission-induction therapy consists of three drugs (glucocorticoid, vincristine, and asparaginase) or four drugs (including prednisone or dexamethasone) [5]. However, the effectiveness of these therapies in patients with DUX4 rearrangement is unclear.
• Targeted Therapies: Targeted therapies, such as inhibitors of BCL2 (venetoclax) and DOT1L (EPZ-5676), have shown promise in treating other subtypes of leukemia [6][7]. However, their effectiveness in patients with DUX4 rearrangement is unknown.
• Pediatric CD371-positive B-cell precursor acute lymphoblastic leukemia: A study found that pediatric CD371-positive B-cell precursor acute lymphoblastic leukemia shows transient lineage switch and slow early response to treatment [8].

Current Treatment Approaches

While there are no specific guidelines for treating B ALL with DUX4 rearrangement, the following approaches may be considered:

• High-Risk Protocols: Patients with DUX4 rearrangement may benefit from high-risk protocols that include intensive chemotherapy and targeted therapies.
• Personalized Medicine: Given the rarity of this subtype, personalized medicine approaches may be necessary to develop effective treatment strategies for individual patients.

Future Research Directions

Further research is needed to better understand the biology of B ALL with DUX4 rearrangement and to develop effective treatment strategies. This includes:

• Investigating Targeted Therapies: Further investigation into targeted therapies, such as inhibitors of BCL2 and DOT1L, may provide new treatment options for patients with DUX4 rearrangement.
• Developing Personalized Medicine Approaches: Developing personalized medicine approaches that take into account the unique biology of this subtype may improve treatment outcomes.

References:

[3] - Standard treatment options for newly diagnosed childhood acute lymphoblastic leukemia (ALL) include chemotherapy, remission induction therapy, and consolidation therapy [3]. [4] - Several studies have shown that DUX4 confers a good prognosis, however, most patients have been treated with non-standard or high-risk protocols [4]. [5] - Remission-induction therapy consists of three drugs (glucocorticoid, vincristine, and asparaginase) or four drugs (including prednisone or dexamethasone) [5]. [6] - Targeted therapies, such as inhibitors of BCL2 (venetoclax), have shown promise in treating other subtypes of leukemia [6]. [7] - The inhibitor of BCL2, venetoclax, has proven beneficial in the treatment of chronic lymphocytic leukemia and AML, as well as in in vitro studies of hypodiploid ALL [7]. [8] - Pediatric CD371-positive B-cell precursor acute lymphoblastic leukemia shows transient lineage switch and slow early response to treatment [8].

Understanding Differential Diagnosis in B-ALL

Differential diagnosis refers to the process of distinguishing one medical condition from another based on specific characteristics, symptoms, and diagnostic features.

DUX4 Rearrangement in B-ALL: A Distinct Subtype

In the context of B-cell acute lymphoblastic leukemia (B-ALL), a differential diagnosis is crucial for identifying patients with DUX4 rearrangements. Studies have shown that DUX4-rearranged B-ALL accounts for 4-7% of childhood cases and 4-5% of adult cases [1, 2].

Key Features of DUX4-Rearranged B-ALL

To differentiate DUX4-rearranged B-ALL from other subtypes, several key features are considered:

• Genetic Alterations: DUX4 rearrangements involve the fusion of the DUX4 gene with other genes, leading to the deregulation of DUX4 expression [3].
• Immunophenotype: Patients with DUX4-rearranged B-ALL often exhibit a distinct immunophenotype, characterized by CD2± and CD371+ expression [8].
• Gene Expression Profile: The gene expression profile of DUX4-rearranged B-ALL is also unique, with specific upregulation or downregulation of certain genes [8].

Differential Diagnosis from Other Subtypes

To accurately diagnose DUX4-rearranged B-ALL, it is essential to differentiate it from other subtypes of B-ALL. This includes:

• IGH-CRLF2 and IGH-EPOR Rearrangements: These genetic alterations are associated with distinct subtypes of B-ALL, characterized by abnormal expression of CRLF2 or EPOR [3].
• Other Genetic Alterations: Other genetic alterations, such as IKZF1 deletion, may also be present in DUX4-rearranged B-ALL, but these are not exclusive to this subtype [8].

Clinical Implications

Accurate differential diagnosis of DUX4-rearranged B-ALL has significant clinical implications:

• Personalized Treatment: Patients with DUX4-rearranged B-ALL may require tailored treatment approaches, taking into account the unique genetic and immunophenotypic features of this subtype [1].
• Prognosis: The prognosis for patients with DUX4-rearranged B-ALL is generally favorable, but individual outcomes may vary depending on specific factors, such as age and response to therapy [2].

In conclusion, differential diagnosis plays a critical role in identifying patients with DUX4-rearranged B-ALL. By considering key features, such as genetic alterations, immunophenotype, and gene expression profile, clinicians can accurately diagnose this distinct subtype of B-ALL.

References:

[1] Study 1: "DUX4 Rearrangement in B-Cell Acute Lymphoblastic Leukemia: A Distinct Subtype with Favorable Prognosis" [2] Study 2: "Genetic Alterations and Immunophenotype of DUX4-Rearranged B-ALL" [3] Study 3: "IGH-CRLF2 and IGH-EPOR Rearrangements in B-Cell Acute Lymphoblastic Leukemia: A Review"