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@ARTICLE{Waclawiczek:274189,
      author       = {A. Waclawiczek$^*$ and A.-M. Leppä$^*$ and S. Renders$^*$
                      and K. Stumpf$^*$ and C. Reyneri$^*$ and B. Betz$^*$ and M.
                      Janssen and R. Shahswar and E. Donato$^*$ and D. Karpova$^*$
                      and V. Thiel$^*$ and J. M. Unglaub and S. Grabowski and S.
                      Gryzik and L. Vierbaum and R. Schlenk$^*$ and C. Rollig and
                      M. Hundemer and C. Pabst and M. Heuser and S. Raffel and C.
                      Muller-Tidow and T. Sauer and A. Trumpp$^*$},
      title        = {{C}ombinatorial {BCL}-2 family expression in {A}cute
                      {M}yeloid {L}eukemia {S}tem {C}ells predicts clinical
                      response to {A}zacitidine/{V}enetoclax.},
      journal      = {Cancer discovery},
      volume       = {13},
      number       = {6},
      issn         = {2159-8274},
      address      = {Philadelphia, Pa.},
      reportid     = {DKFZ-2023-00484},
      pages        = {1408-1427},
      year         = {2023},
      note         = {#EA:A010#LA:A010# / 2023 Jun 2;13(6):1408-1427},
      abstract     = {The BCL-2 inhibitor Venetoclax (VEN) in combination with
                      Azacitidine (5-AZA) is currently transforming Acute Myeloid
                      Leukemia (AML) therapy. However, there is a lack of
                      clinically relevant biomarkers that predict response to
                      5-AZA/VEN. Here, we integrated transcriptomic, proteomic,
                      functional and clinical data to identify predictors of
                      5-AZA/VEN response. Although cultured monocytic AML cells
                      displayed upfront resistance, monocytic differentiation was
                      not clinically predictive in our patient cohort. We
                      identified leukemic stem cells (LSC) as primary targets of
                      5-AZA/VEN whose elimination determined therapy outcome. LSCs
                      of 5-AZA/VEN refractory patients displayed perturbed
                      apoptotic dependencies. We developed and validated a flow
                      cytometry-based 'Mediators-of-Apoptosis-Combinatorial-Score'
                      (MAC-Score) linking the ratio of protein expression of
                      BCL-2, BCL-xL, and MCL-1 in LSCs. MAC-Scoring predicts
                      initial response with a positive predictive-value of $>97\%$
                      associated to increased event-free survival. In summary,
                      combinatorial levels of BCL-2-family members in AML-LSCs are
                      a key denominator of response and MAC-Scoring reliably
                      predicts patient response to 5-AZA/VEN.},
      cin          = {A010 / HD01 / W010},
      ddc          = {610},
      cid          = {I:(DE-He78)A010-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)W010-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36892565},
      doi          = {10.1158/2159-8290.CD-22-0939},
      url          = {https://inrepo02.dkfz.de/record/274189},
}