A complex interplay of intra- and extracellular factors regulates the outcome of fetal- and adult-derived MLL-rearranged leukemia
(2024) In Leukemia- Abstract
Infant and adult MLL1/KMT2A-rearranged (MLLr) leukemia represents a disease with a dismal prognosis. Here, we present a functional and proteomic characterization of in utero-initiated and adult-onset MLLr leukemia. We reveal that fetal MLL::ENL-expressing lymphomyeloid multipotent progenitors (LMPPs) are intrinsically programmed towards a lymphoid fate but give rise to myeloid leukemia in vivo, highlighting a complex interplay of intra- and extracellular factors in determining disease subtype. We characterize early proteomic events of MLL::ENL-mediated transformation in fetal and adult blood progenitors and reveal that whereas adult pre-leukemic cells are mainly characterized by retained myeloid features and downregulation of ribosomal... (More)
Infant and adult MLL1/KMT2A-rearranged (MLLr) leukemia represents a disease with a dismal prognosis. Here, we present a functional and proteomic characterization of in utero-initiated and adult-onset MLLr leukemia. We reveal that fetal MLL::ENL-expressing lymphomyeloid multipotent progenitors (LMPPs) are intrinsically programmed towards a lymphoid fate but give rise to myeloid leukemia in vivo, highlighting a complex interplay of intra- and extracellular factors in determining disease subtype. We characterize early proteomic events of MLL::ENL-mediated transformation in fetal and adult blood progenitors and reveal that whereas adult pre-leukemic cells are mainly characterized by retained myeloid features and downregulation of ribosomal and metabolic proteins, expression of MLL::ENL in fetal LMPPs leads to enrichment of translation-associated and histone deacetylases signaling proteins, and decreased expression of inflammation and myeloid differentiation proteins. Integrating the proteome of pre-leukemic cells with their secretome and the proteomic composition of the extracellular environment of normal progenitors highlights differential regulation of Igf2 bioavailability, as well as of VLA-4 dimer and its ligandome, upon initiation of fetal- and adult-origin leukemia, with implications for human MLLr leukemia cells’ ability to communicate with their environment through granule proteins. Our study has uncovered opportunities for targeting ontogeny-specific proteomic vulnerabilities in in utero-initiated and adult-onset MLLr leukemia.
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- author
- Jassinskaja, Maria LU ; Ghosh, Sudip LU ; Watral, Joanna LU ; Davoudi, Mina LU ; Claesson Stern, Melina ; Daher, Ugarit LU ; Eldeeb, Mohamed LU ; Zhang, Qinyu LU ; Bryder, David LU and Hansson, Jenny LU
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- epub
- subject
- in
- Leukemia
- publisher
- Nature Publishing Group
- external identifiers
-
- scopus:85188996417
- pmid:38555405
- ISSN
- 0887-6924
- DOI
- 10.1038/s41375-024-02235-5
- language
- English
- LU publication?
- yes
- id
- ba380567-f6b2-41d9-b1ac-c077b26a8bfb
- date added to LUP
- 2024-04-16 15:36:36
- date last changed
- 2024-07-17 03:00:16
@article{ba380567-f6b2-41d9-b1ac-c077b26a8bfb, abstract = {{<p>Infant and adult MLL1/KMT2A-rearranged (MLLr) leukemia represents a disease with a dismal prognosis. Here, we present a functional and proteomic characterization of in utero-initiated and adult-onset MLLr leukemia. We reveal that fetal MLL::ENL-expressing lymphomyeloid multipotent progenitors (LMPPs) are intrinsically programmed towards a lymphoid fate but give rise to myeloid leukemia in vivo, highlighting a complex interplay of intra- and extracellular factors in determining disease subtype. We characterize early proteomic events of MLL::ENL-mediated transformation in fetal and adult blood progenitors and reveal that whereas adult pre-leukemic cells are mainly characterized by retained myeloid features and downregulation of ribosomal and metabolic proteins, expression of MLL::ENL in fetal LMPPs leads to enrichment of translation-associated and histone deacetylases signaling proteins, and decreased expression of inflammation and myeloid differentiation proteins. Integrating the proteome of pre-leukemic cells with their secretome and the proteomic composition of the extracellular environment of normal progenitors highlights differential regulation of Igf2 bioavailability, as well as of VLA-4 dimer and its ligandome, upon initiation of fetal- and adult-origin leukemia, with implications for human MLLr leukemia cells’ ability to communicate with their environment through granule proteins. Our study has uncovered opportunities for targeting ontogeny-specific proteomic vulnerabilities in in utero-initiated and adult-onset MLLr leukemia.</p>}}, author = {{Jassinskaja, Maria and Ghosh, Sudip and Watral, Joanna and Davoudi, Mina and Claesson Stern, Melina and Daher, Ugarit and Eldeeb, Mohamed and Zhang, Qinyu and Bryder, David and Hansson, Jenny}}, issn = {{0887-6924}}, language = {{eng}}, publisher = {{Nature Publishing Group}}, series = {{Leukemia}}, title = {{A complex interplay of intra- and extracellular factors regulates the outcome of fetal- and adult-derived MLL-rearranged leukemia}}, url = {{http://dx.doi.org/10.1038/s41375-024-02235-5}}, doi = {{10.1038/s41375-024-02235-5}}, year = {{2024}}, }