Details

Autor(en) / Beteiligte

• Li, Yanan
• Yang, Wei
• Patel, Riddhi M.
• Casey, Emily B.
• Denby, Elisabeth
• Mendoza-Castrejon, Jonny
• Rodriguez-Lopez, Priscilla
• Magee, Jeffrey A.

Titel

FLT3ITD drives context-specific changes in cell identity and variable interferon dependence during AML initiation

Ist Teil von

• Blood, 2023-03, Vol.141 (12), p.1442-1456

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• •Flt3ITD activates distinct transcriptional programs via distinct enhancers when it cooperates with NUP98 and Runx1 mutations.•Flt3ITD and NUP98-HOXD13 selectively activate type I interferon signaling and thus create a context-specific pathway dependency. [Display omitted] Acute myeloid leukemia (AML) initiation requires multiple rate-limiting mutations to cooperatively reprogram progenitor cell identity. For example, FLT3 internal tandem duplication (FLT3ITD) mutations cooperate with a variety of different initiating mutations to reprogram myeloid progenitor fate. These initiating mutations often skew toward either pediatric or adult AML patient populations, though FLT3ITD itself occurs at similar frequencies in both age groups. This raises the question of whether FLT3ITD might induce distinct transcriptional programs and unmask distinct therapeutic vulnerabilities when paired with pediatric, as opposed to adult AML-initiating mutations. To explore this possibility, we compared AML evolution in mice that carried Flt3ITD/NUP98-HOXD13 (NHD13) or Flt3ITD/Runx1DEL mutation pairs, which are respectively most common in pediatric and adult AML. Single-cell analyses and epigenome profiling revealed distinct interactions between Flt3ITD and its cooperating mutations. Whereas Flt3ITD and Flt3ITD/Runx1DEL caused aberrant expansion of myeloid progenitors, Flt3ITD/NHD13 drove the emergence of a pre-AML population that did not resemble normal hematopoietic progenitors. Differences between Flt3ITD/Runx1DEL and Flt3ITD/NHD13 cooperative target gene expression extended to fully transformed AML as well. Flt3ITD/NHD13 cooperative target genes were enriched in human NUP98-translocated AML. Flt3ITD/NHD13 selectively hijacked type I interferon signaling to drive expansion of the pre-AML population. Blocking interferon signaling delayed AML initiation and extended survival. Thus, common AML driver mutations, such as FLT3ITD, can coopt different mechanisms of transformation in different genetic contexts. Furthermore, pediatric-biased NUP98 fusions convey actionable interferon dependence. Leukemic driver gene alterations that co-occur with FLT3 internal tandem duplication (FLT3ITD) in acute myeloid leukemia (AML) vary with age; chromosomal rearrangements are more common in children and single-gene mutations, such as DNMT3A, and RUNX1 loss of function mutations are more common in adult AML. Li and colleagues explore the significance of those observations using murine models with complementary transcriptomic, epigenetic, and functional studies. The authors reveal that the functional consequences of FLT3ITD signaling are dynamic, demonstrating age-, cell-type–, and comutation-specific dependencies, which help explain divergent clinical phenotypes.