HOXB4 – Acute Myeloid Leukemia

In recent studies, altered expression of HOXB4 (HGNC:5115) has been shown to be associated with acute myeloid leukemia (AML) (MONDO:0018874). In a multi‐patient study including 83 de novo AML patients (PMID:35782688), low HOXB4 expression was found to correlate with lower complete remission rates, increased relapse, and shorter overall and disease‐free survival. These findings contribute to a strong genetic association between HOXB4 expression levels and clinical outcomes in AML.

Although classical Mendelian segregation is not observed in this predominantly somatic disease, the study findings support that altered HOXB4 expression collectively in a sizeable cohort (83 patients PMID:35782688) provides robust genetic evidence. A representative variant, reported as c.772_790del (p.Ser258TrpfsTer39), is included to highlight the type of coding changes observed in molecular studies, further emphasizing the relevance of HOXB4 in these assays.

Complementary functional studies have provided mechanistic insight into the pathogenicity associated with HOXB4 dysregulation. In an in vitro and in vivo assessment (PMID:15226173), HOXB4 overexpression was shown to enhance hematopoietic stem cell self-renewal in a DNA-binding dependent manner. Mutants lacking DNA-binding capacity failed to promote expansion of bone marrow cells, underscoring the importance of HOXB4’s transcriptional activity in hematopoiesis and by extension in leukemogenesis.

Notably, additional studies have also explored the interaction of HOXB4 with other homeobox genes. For instance, an investigation using bioinformatics and protein-protein interaction analysis highlighted the inter-relationship between HOXB4, HOXB5, and HOXA7, suggesting that complex epigenetic regulation might impact the gene’s prognostic utility (PMID:34421991). While these extra layers of regulation warrant further investigation, they do not detract from the consistent clinical correlations observed across the studies.

The collective data integrating genetic and functional evidence thus firmly support a strong association between HOXB4 and AML. Although the disease’s etiology involves non-germline events, the magnitude of the observed clinical correlations and the consistent demonstration of HOXB4’s mechanistic role in stem cell regulation render it a promising biomarker for risk stratification and potential therapeutic targeting.

Key take‐home: HOXB4 stands out as a robust molecular candidate with strong clinical utility for prognostic assessment in acute myeloid leukemia.

References

• Pharmacogenomics and personalized medicine • 2022 • Impact of HOXB4 and PRDM16 Gene Expressions on Prognosis and Treatment Response in Acute Myeloid Leukemia Patients PMID:35782688
• Frontiers in genetics • 2021 • The Prognostic Value and Function of HOXB5 in Acute Myeloid Leukemia PMID:34421991
• Blood • 2004 • Molecular interactions involved in HOXB4-induced activation of HSC self-renewal PMID:15226173

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