Biology subjects

Knaevelsrud, H.

Publications and source records attributed to Knaevelsrud, H..

5 recordsLinked to original sources

bioRxiv2026

The human leukemic fusion protein MLL-AF4 promotes autophagy and cell death in the fat body of Drosophila melanogaster

MLL-rearranged (MLLr) leukemia is an aggressive form of acute leukemia driven by chromosomal translocations fusing MLL with one of more than 100 partner genes, most commonly AF4. We previously showed that expression of the human MLL-AF4 fusion protein in the larval hematopoietic system of Drosophila melanogaster promotes hyperproliferation. Here, we report that the same oncogene elicits a strikingly opposite response in the larval fat body, inducing cell shrinkage, autophagy, and caspase-dependent cell death in a manner dependent on the intact fusion protein. Autophagy induction preceded caspase activation, yet the two programs operated in parallel rather than in series. Mechanistically, MLL-AF4-expressing fat body cells displayed elevated AMPK phosphorylation and reduced mTORC1 activity, and depletion of AMPK abolished caspase activation. Despite producing opposite phenotypes, both tissue-specific responses depended on conserved complex partners, suggesting that MLL-AF4 co-opts a shared mechanism to produce starkly different outcomes depending on cellular context. Uncovering how MLL-AF4 induces apoptosis-like phenotypes in the fat body could potentially be used to rewire leukemic signaling and remove malignant cells.

cancer biology↗

bioRxiv2026

SQSTM1/p62 accumulation is a hallmark of FLCN loss in Birt-Hogg-Dube syndrome-associated kidney cancer

Birt-Hogg-Dube syndrome (BHD) is an autosomal, dominant condition caused by Folliculin (FLCN) mutation and characterized by enhanced risk for kidney tumors. Previous studies have shown constitutive nuclear localization of the transcription factor TFEB and simultaneous hyperactivation of canonical MTORC1 signaling in the absence of FLCN. Here we assess the impact on autophagy under this situation of combined anabolic and catabolic activation. Using an established BHD patient-derived kidney cancer cell line, we confirmed that TFEB was permanently localized in the nucleus combined with an increase in canonical MTORC1 signaling, whereas bulk autophagy flux and LC3 lipidation was unaffected by FLCN status. However, we found that the autophagy receptor SQSTM1/p62 accumulated in enlarged puncta in the absence of FLCN. Finally, we recapitulate these findings in a Norwegian cohort of BHD kidney tumor samples. Our results demonstrate SQSTM1/p62 accumulation as a hallmark of FLCN loss, although SQSTM1/p62 appeared dispensable for anchorage-independent growth.

cancer biology↗

bioRxiv2025

Interaction of HS1BP3 with cortactin modulates TKS5 localisation and cancer malignancy

We have previously shown that HS1BP3 interacts with the SH3 domain of cortactin, a protein that contributes to a malignant phenotype in cancers. Here we demonstrate that high expression of HS1BP3 is predictive of poorer outcomes for gastric adenocarcinoma and triple negative breast carcinoma patients. We mapped the HS1BP3-SH3 interaction site to the third proline rich region (PRR3.1) of HS1BP3 and show that cells expressing an HS1BP3 PRR3.1 mutant failed to rescue the reduced proliferation and matrix degradation observed in HS1BP3 depleted cells. Moreover, the HS1BP3 PRR3.1 mutant was found to modulate the mRNA levels of the invadopodia scaffold protein TKS5 in gastric cancer cells and contribute to buildup of TKS5 inside multivesicular endosomes in both gastric and TNBC cells. Overall, our results highlight the importance of the direct interaction between the HS1BP3 PRR3.1 and the cortactin SH3 domain in cancer development by regulating endosomal trafficking and cytoskeleton arrangements.

cell biology↗

bioRxiv2022

The human leukemic oncogene MLL-AF4 promotes hyperplastic growth of hematopoietic tissues in Drosophila larvae

MLL-rearranged leukemias are among the leukemic subtypes with poorest survival, and treatment options have barely improved over the last decades. Furthermore, despite increasing molecular understanding of the mechanisms behind these hematopoietic malignancies, this knowledge has had poor translation into the clinic. Identification of novel treatment methods is hampered by the lack of relevant in vivo models that allow for rapid identification of actionable drug targets and small molecule inhibitors. Here, we report a Drosophila melanogaster model system to explore the pathways affected in MLL-rearranged leukemia. We show that expression of the human leukemic oncogene MLL-AF4 in the Drosophila hematopoietic system resulted in increased levels of circulating hemocytes and an enlargement of the larval hematopoietic organ, the lymph gland. Strikingly, depletion of Drosophila orthologs of known interactors of MLL-AF4, such as DOT1L, rescued the leukemic phenotype. In agreement, treatment with small-molecule inhibitors of DOT1L also prevented the MLL-AF4-induced leukemia-like phenotype. Taken together, this model provides an in vivo system to unravel the genetic interactors involved in leukemogenesis and offers a strategy for a prompt identification of potential therapeutic options for treatment of MLL-rearranged leukemia.

cancer biology↗

bioRxiv2020

Rala and the exocyst control Pvr trafficking and signaling to ensure lymph gland homeostasis in Drosophila melanogaster

The balance between hematopoietic progenitors and differentiated hemocytes is finely tuned during development. In the larval hematopoietic organ of Drosophila, called the lymph gland, the receptor tyrosine kinase Pvr signals from differentiated cells to maintain a pool of undifferentiated progenitors. However, little is known about the processes that support Pvr function. The small GTPase Ral is involved in the regulation of several membrane trafficking events. Drosophila has a single Ral protein, Rala, which has been implicated in the development of various tissues. Here, we investigated the involvement of Rala in the larval fly hematopoietic system. We discovered that the loss of Rala activity phenocopies Pvr loss of function by promoting hemocyte progenitor differentiation. Moreover, using epistasis analysis, we found that the guanine exchange factor RalGPS lies upstream of Rala in this event, whereas the exocyst and Rab11 are acting downstream. Strikingly, the loss of Rala activity leads to a considerable accumulation of Pvr at the plasma membrane, hence suggesting a trafficking defect and reduced Pvr function. Consistent with this hypothesis, Rala loss of function phenotype in the lymph gland is fully suppressed by constitutive STAT activity, which normally mediates Pvr function in the lymph gland. Together, our findings unravel a novel RalGPS-Rala-exocyst-Rab11 axis for the maintenance of lymph gland homeostasis through Pvr.

developmental biology↗