Intracellular iron homeostasis-regulated epigenetic reprogramming contributes to -7/del(7q) leukemia

Area of Science:

• Oncology
• Epigenetics
• Hematopoiesis

Background:

• Chromosome copy number variations, like deletion of chromosome 7 (-7/del(7q)), are key drivers of acute myeloid leukemia (AML) and are associated with poor prognosis.
• The 7q region is known to harbor tumor suppressor genes, with KMT2C previously identified as one such gene.

Purpose of the Study:

• To identify novel tumor suppressors within the -7/del(7q) region in acute myeloid leukemia.
• To elucidate the functional role of ABCB8 in hematopoietic stem and progenitor cell differentiation and leukemogenesis.

Main Methods:

• A differentiation CRISPR screen was employed in hematopoietic stem and progenitor cells.
• In vivo leukemogenesis models were used to assess the impact of ABCB8 deficiency.
• Iron homeostasis and epigenetic modifications, including H3K27me3 levels, were analyzed.

Main Results:

• The mitochondrial iron transporter ABCB8 was identified as essential for hematopoietic stem and progenitor cell differentiation.
• ABCB8 deficiency accelerated leukemogenesis, disrupted iron homeostasis, and impaired iron-dependent enzymes like KDM6A.
• Loss of ABCB8 led to elevated H3K27me3 levels, repressing differentiation genes in an iron- and KDM6A-dependent manner.

Conclusions:

• ABCB8 functions as a tumor suppressor in -7/del(7q) acute myeloid leukemia.
• ABCB8 and KMT2C, located adjacently on chromosome 7q, cooperate to regulate H3K27me3 and suppress leukemogenesis.
• The findings highlight an epigenetic collaboration between neighboring tumor suppressors, mediated by iron-dependent chromatin remodeling.