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A complex interplay of intra- and extracellular factors regulates the outcome of fetal- and adult-derived MLL-rearranged leukemia

Jassinskaja, Maria LU ; Ghosh, Sudip LU ; Watral, Joanna LU ; Davoudi, Mina LU orcid ; Claesson Stern, Melina ; Daher, Ugarit LU ; Eldeeb, Mohamed LU ; Zhang, Qinyu LU ; Bryder, David LU and Hansson, Jenny LU orcid (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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; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Leukemia
publisher
Nature Publishing Group
external identifiers
  • pmid:38555405
  • scopus:85188996417
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
2024-04-17 03:00:05
@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}},
}