bims-tremyl 2022-01-23 papers

on Therapy resistance biology in myeloid leukemia

Issue of 2022‒01‒23
twenty-five papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London

Impact of FLT3 mutation on outcomes after venetoclax and azacitidine for patients with treatment-naive acute myeloid leukemia.
Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications.
Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells.
Subversion of serotonin-receptor signaling in osteoblasts by kynurenine drives Acute Myeloid Leukemia.
Measurable residual disease, FLT3-ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1-mutated acute myeloid leukemia.
TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity.
Impact of Venetoclax and Azacitidine in Treatment-Naive Patients with Acute Myeloid Leukemia and IDH1/2 mutations.
Novel inhibitor of hematopoietic cell kinase as a potential therapeutic agent for acute myeloid leukemia.
C/EBPβ sustains the oncogenic program of AML cells by cooperating with MYB and co-activator p300 in a transcriptional module.
Uncoupling the BMP receptor antagonist function from the WNT agonist function of R-spondin 2 using the inhibitory peptide dendrimer RWd.
Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs.
European LeukemiaNet-defined primary refractory acute myeloid leukemia: the value of allogeneic hematopoietic stem cell transplant and overall response.
Outcomes based on treatment setting in refractory acute myeloid leukemia and other high-grade myeloid malignancies.
Changing paradigms in the treatment of acute myeloid leukemia in older patients.
Prospect of CAR T-cell therapy in acute myeloid leukemia.
Life histories of myeloproliferative neoplasms inferred from phylogenies.
Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation.
Reduced intensity hematopoietic stem cell transplantation for myelofibrosis in accelerated-phase.
Improved relative survival in older patients with acute myeloid leukemia over a 30-year period in the Netherlands: a long haul is needed to change nothing into something.
The Elephant in The Room: AML Relapse Post Allogeneic Hematopoietic Cell Transplantation.
SFPQ-ABL1 and BCR-ABL1 utilize different signalling networks to drive B-cell acute lymphoblastic leukaemia.
Structural Racism is a Mediator of Disparities in Acute Myeloid Leukemia Outcomes.
Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2.
Implications of Clonal Hematopoiesis for Precision Oncology.
Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants.

Clin Cancer Res. 2022 Jan 21. pii: clincanres.3405.2021. [Epub ahead of print]

Impact of FLT3 mutation on outcomes after venetoclax and azacitidine for patients with treatment-naive acute myeloid leukemia.

Marina Konopleva, Michael J Thirman, Keith W Pratz, Jacqueline S Garcia, Christian Recher, Vinod Pullarkat, Hagop M Kantarjian, Courtney D DiNardo, Monique Dail, Yinghui Duan, Brenda Chyla, Jalaja Potluri, Catherine L Miller, Andrew H Wei.

PURPOSE: Evaluate efficacy and safety of venetoclax+azacitidine among treatment-naïve patients with FLT3 mutant acute myeloid leukemia.PATIENTS AND METHODS: Data were pooled from patients enrolled in a Phase 3 study (NCT02993523) that compared patients treated with venetoclax+azacitidine or placebo+azacitidine and a prior Phase 1b study (NCT02203773) where patients were treated with venetoclax+azacitidine. Enrolled patients were ineligible for intensive therapy due to age {greater than or equal to}75 years and/or co-morbidities. Patients on venetoclax+azacitidine received Ven 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle). FLT3 mutation was analyzed centrally on pretreatment bone marrow aspirates.
RESULTS: In the biomarker evaluable population, FLT3 mutation was detected in 42 (15%) and 22 (19%) patients in the venetoclax+azacitidine and azacitidine groups. Composite complete remission (CRc, complete remission [CR]+CR with incomplete hematologic recovery [CRi]) rates (venetoclax+azacitidine /azacitidine) for FLT3 mutant patients were 67%/36%, median duration of remission (DoR) was 17.3/5.0 months, and median OS was 12.5/8.6 months. The CRc rates among FLT3 wild-type were 67%/25%, median DoR 18.4/13.4 months, and median OS 14.7/10.1 months. In patients treated with venetoclax+azacitidine, CRc in patients with FLT3-ITD and FLT3-TKD was 63% and 77%, median OS was 9.9 and 19.2 months, and in co-mutated FLT3-ITD+NPM1, CRc was 70%, median DoR was not reached, and median OS was 9.1 months. There were no unexpected toxicities in the venetoclax+azacitidine group.
CONCLUSION: When treated with venetoclax+azacitidine, patients with FLT3 mutations and FLT3 wild-type had similar outcomes. Future analyses in larger patient populations may further define the impact of venetoclax+azacitidine in patients harboring FLT3-ITD.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-3405
Stem Cell Rev Rep. 2022 Jan 20.

Acute Myeloid Leukemia Stem Cells: Origin, Characteristics, and Clinical Implications.

Nathaniel A Long, Upendarrao Golla, Arati Sharma, David F Claxton.

  The stem cells of acute myeloid leukemia (AML) are the malignancy initiating cells whose survival ultimately drives growth of these lethal diseases. Here we review leukemia stem cell (LSC) biology, particularly as it relates to the very heterogeneous nature of AML and to its high disease relapse rate. Leukemia ontogeny is presented, and the defining functional and phenotypic features of LSCs are explored. Surface and metabolic phenotypes of these cells are described, particularly those that allow distinction from features of normal hematopoietic stem cells (HSCs). Opportunities for use of this information for improving therapy for this challenging group of diseases is highlighted, and we explore the clinical needs which may be addressed by emerging LSC data. Finally, we discuss current gaps in the scientific understanding of LSCs.

Keywords:  Acute Myeloid Leukemia; Hematopoiesis; Leukemia; Leukemia Stem Cell

DOI:  https://doi.org/10.1007/s12015-021-10308-6
Cancers (Basel). 2022 Jan 17. pii: 453. [Epub ahead of print]14(2):

Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells.

Marine Dupont, Mathilde Huart, Claire Lauvinerie, Audrey Bidet, Amélie Valérie Guitart, Arnaud Villacreces, Isabelle Vigon, Vanessa Desplat, Ali El Habhab, Arnaud Pigneux, Zoran Ivanovic, Philippe Brunet De la Grange, Pierre-Yves Dumas, Jean-Max Pasquet.

  Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate.

Keywords:  FLT3-ITD; acute myeloid leukemia; autophagy; leukemic initiating cells; persistence; tyrosine kinase inhibitors

DOI:  https://doi.org/10.3390/cancers14020453
Cancer Discov. 2022 Jan 19. pii: candisc.0692.2021. [Epub ahead of print]

Subversion of serotonin-receptor signaling in osteoblasts by kynurenine drives Acute Myeloid Leukemia.

Marta Galan-Diez, Florence Borot, Abdullah Mahmood Ali, Junfei Zhao, Eva Gil-Iturbe, Xiaochuan Shan, Na Luo, Yongfeng Liu, Xi-Ping Huang, Brygida Bisikirska, Rossella Labella, Irwin Kurland, Bryan L Roth, Matthias Quick, Siddhartha Mukherjee, Raul Rabadan, Martin Carroll, Azra Raza, Stavroula Kousteni.

Remodeling of the microenvironment by tumor cells can activate pathways that favor cancer growth. Molecular delineation and targeting of such malignant-cell non-autonomous pathways may help overcome resistance to targeted-therapies. Herein we leverage genetic mouse models, patient-derived xenografts, and patient samples to show that acute myeloid leukemia (AML) exploits peripheral serotonin-signaling to remodel the endosteal niche to its advantage. AML progression requires the presence of serotonin receptor-1b (HTR1B) in osteoblasts and is driven by AML-secreted kynurenine, which acts as an oncometabolite and HTR1B ligand. AML cells utilize kynurenine to induce a pro-inflammatory state in osteoblasts which, through the acute-phase protein serum amyloid A (SAA), acts in a positive feedback-loop on leukemia cells by increasing expression of IDO1 -the rate-limiting enzyme for kynurenine synthesis-, thereby enabling AML progression. This leukemia-osteoblast crosstalk, conferred by the kynurenine-HTR1B-SAA-IDO1 axis, could be exploited as a niche-focused therapeutic approach against AML, opening new avenues for cancer treatment.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0692
Cancer Med. 2022 Jan 20.

Measurable residual disease, FLT3-ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1-mutated acute myeloid leukemia.

Rama Al Hamed, Myriam Labopin, Etienne Daguindau, Riitta Niittyvuopio, Anne Huynh, Gerard Socié, Micha Srour, Jean Henri Bourhis, Nicolaus Kröger, Eleni Tholouli, Goda Choi, Xavier Poiré, Hans Martin, Marie-Thérèse Rubio, Pavel Jindra, Didier Blaise, Dietrich Beelen, Hélène Labussière-Wallet, Arnon Nagler, Ali Bazarbachi, Mohamad Mohty.

  Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified 1572 adult (age ≥ 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow-up for survivors was 23.7 months. FLT3-ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia-free survival (LFS) were negatively affected by concomitant FLT3-ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p < 0.0001, respectively), MRD positivity at transplant (HR 2.18, p < 10-5 and HR 1.71, p < 10-5 , respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score ≥90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3-ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p < 10-5 ), and older age (HR 1.22 per 10 years, p < 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score ≥90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3-ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1-mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.

Keywords:  FLT3-ITD; NPM-1 mutation; acute myeloid leukemia; minimal residual disease

DOI:  https://doi.org/10.1002/cam4.4218
Cell Stem Cell. 2022 Jan 11. pii: S1934-5909(21)00491-4. [Epub ahead of print]

TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity.

Tomoya Muto, Maria Guillamot, Jennifer Yeung, Jing Fang, Joshua Bennett, Bettina Nadorp, Audrey Lasry, Luna Zea Redondo, Kwangmin Choi, Yixiao Gong, Callum S Walker, Kathleen Hueneman, Lyndsey C Bolanos, Laura Barreyro, Lynn H Lee, Kenneth D Greis, Nikita Vasyliev, Alireza Khodadadi-Jamayran, Evgeny Nudler, Amaia Lujambio, Scott W Lowe, Iannis Aifantis, Daniel T Starczynowski.

  Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of pre-leukemic cells that acquire specific mutations. Although individuals with CH are healthy, they are at an increased risk of developing myeloid malignancies, suggesting that additional alterations are needed for the transition from a pre-leukemia stage to frank leukemia. To identify signaling states that cooperate with pre-leukemic cells, we used an in vivo RNAi screening approach. One of the most prominent genes identified was the ubiquitin ligase TRAF6. Loss of TRAF6 in pre-leukemic cells results in overt myeloid leukemia and is associated with MYC-dependent stem cell signatures. TRAF6 is repressed in a subset of patients with myeloid malignancies, suggesting that subversion of TRAF6 signaling can lead to acute leukemia. Mechanistically, TRAF6 ubiquitinates MYC, an event that does not affect its protein stability but rather represses its functional activity by antagonizing an acetylation modification.

Keywords:  AML; MDS; MPN; MYC; TRAF6; clonal hematopoiesis; hematopoiesis; inflammation; innate immune signaling; myeloid malignancies; ubiquitination

DOI:  https://doi.org/10.1016/j.stem.2021.12.007
Clin Cancer Res. 2022 Jan 19. pii: clincanres.3467.2021. [Epub ahead of print]

Impact of Venetoclax and Azacitidine in Treatment-Naive Patients with Acute Myeloid Leukemia and IDH1/2 mutations.

Daniel A Pollyea, Courtney D DiNardo, Martha L Arellano, Arnaud Pigneux, Walter Fiedler, Marina Konopleva, David A Rizzieri, B Douglas Smith, Atushi Shinagawa, Roberto M Lemoli, Monique Dail, Yinghui Duan, Brenda Chyla, Jalaja Potluri, Catherine L Miller, Hagop M Kantarjian.

PURPOSE: Evaluate efficacy and safety of venetoclax+azacitidine among treatment-naïve patients with IDH1/2 mutant (mut) AML.PATIENTS AND METHODS: Data were pooled from patients enrolled in a Phase 3 study (NCT02993523) that compared patients treated with venetoclax+azacitidine or placebo+azacitidine and a prior Phase 1b study (NCT02203773) where patients were treated with venetoclax+azacitidine. Enrolled patients were ineligible for intensive therapy due to age {greater than or equal to}75 years and/or co-morbidities. Patients on venetoclax+azacitidine received venetoclax 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle).
RESULTS: IDH1/2mut were detected in 81 (26%) and 28 (22%) patients in the venetoclax+azacitidine and azacitidine groups. Composite complete remission (CRc, complete remission [CR]+CR with incomplete hematologic recovery [CRi]) rates (venetoclax+azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In the IDH1mut, CRc rates were 66.7%/9.1% and mOS 15.2/2.2 months. In IDH2mut, CRc were 86.0%/11.1%; mOS not reached (NR)/13.0 months. In IDH1/2 WT AML treated with venetoclax+azacitidine with poor-risk cytogenetics had inferior outcomes compared to IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax+azacitidine group.
CONCLUSION: Patients with IDH1/2mut who receive venetoclax+azacitidine had high response rates, durable remissions and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-3467
Cancer Immunol Immunother. 2022 Jan 18.

Novel inhibitor of hematopoietic cell kinase as a potential therapeutic agent for acute myeloid leukemia.

Fernanda Marconi Roversi, Maura Lima Pereira Bueno, Juliete Aparecida Francisco da Silva, Guilherme Rossi Assis-Mendonça, Cristiane Okuda Torello, Rodrigo Nato Shiraishi, Fernando Viera Pericole, Karla Priscila Ferro, Adriana Santos Silva Duarte, Eduardo Magalhães Rego, Sara Teresinha Olalla Saad.

  Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are characterized by risk of relapses, poor survival, unwanted side effects and high toxicity with the current therapies. In light of these facts, there are efforts to develop new drugs specific for deregulated molecules that participate in leukemia pathogenesis. Hematopoietic cell kinase (HCK), an Src kinase family member, is overexpressed on hematopoietic stem cells of MDS and de novo AML patients and involved in the oncogenic process. Thus, we investigated in vitro, ex vivo and in vivo effects of a novel chemical compound targeting HCK inhibition (iHCK-37), in combination with the most used drugs for the treatment of MDS and de novo AML, 5-Azacytidine and Cytarabine. Herein, the combination treatment with iHCK-37 and 5-Azacytidine or Cytarabine demonstrated additive effects against leukemia cells, compared to either drug alone. iHCK-37 plus 5-Azacytidine or Cytarabine treatment was able to reduce the activation of oncogenic pathways, MAPK/ERK and PI3K/AKT, leading to reduction of ERK and AKT phosphorylation, and increased BAX and decreased BCL-XL protein expression. Moreover, treatment with iHCK-37 reduced MDS and AML CD34-positive cell numbers inside a 3D-structure but did not affect normal CD34-positive cell numbers. In vivo analysis showed that leukemic mice treated with iHCK-37 had reduced ERK and AKT proteins phosphorylation levels and leukocyte numbers. In conclusion, the iHCK-37 inhibitor has anti-neoplastic activity in leukemia cells without altering apoptosis and survival rate of normal cells, suggesting on-target malignant cell killing activity as a single agent or in combination with 5-Azacytidine or Cytarabine.

Keywords:  De novo acute myeloid leukemia; Drug inhibition; Hematopoietic cell kinase; Myelodysplastic syndrome; iHCK-37

DOI:  https://doi.org/10.1007/s00262-021-03111-2
Exp Hematol. 2022 Jan 12. pii: S0301-472X(22)00031-5. [Epub ahead of print]

C/EBPβ sustains the oncogenic program of AML cells by cooperating with MYB and co-activator p300 in a transcriptional module.

Karl-Heinz Klempnauer.

Transcription factor MYB is a key regulator of gene expression in hematopoietic cells and has emerged as a novel drug target for acute myeloid leukemia (AML). Studies aiming to identify potential MYB inhibitors have shown that the natural compound helenalin acetate (HA) inhibits viability and induces cell death and differentiation of AML cells by disrupting the MYB-induced gene expression program. Interestingly, CCAAT-box/enhancer binding protein beta (C/EBPβ), a transcription factor known to cooperate with MYB and the co-activator p300 in myeloid cells, rather than MYB itself, was identified as the primary target of HA. This supports a model in which MYB, C/EBPβ and p300 form the core of a transcriptional module that is essential for the maintenance of proliferative potential of AML cells, highlighting a novel role of C/EBPβ as a pro-leukemogenic factor.

DOI: https://doi.org/10.1016/j.exphem.2022.01.003
J Biol Chem. 2022 Jan 12. pii: S0021-9258(22)00026-6. [Epub ahead of print] 101586

Uncoupling the BMP receptor antagonist function from the WNT agonist function of R-spondin 2 using the inhibitory peptide dendrimer RWd.

Hyeyoon Lee, Rui Sun, Christof Niehrs.

  Signaling by bone morphogenetic proteins (BMPs) plays pivotal roles in embryogenesis, adult tissue homeostasis, and disease. Recent studies revealed that the well-established WNT agonist R-spondin 2 (RSPO2) is also a BMP receptor (BMPR1A) antagonist, with roles in early Xenopus embryogenesis and human acute myeloid leukemia (AML). To uncouple the BMP antagonist function from the WNT agonist function and to promote development of AML therapeutics, here we identified a 10-mer peptide (RW) derived from the Thrombospondin 1 (TSP1)-domain of RSPO2, which specifically prevents binding between RSPO2 and BMPR1A without altering WNT signaling. We also show a corresponding RW-dendrimer (RWd) exhibiting improved half-life relieves inhibition of BMP receptor signaling by RSPO2 in human AML cells, reducing cell growth and inducing differentiation. Moreover, microinjection of RWd in Xenopus embryos ventralizes the dorsoventral embryonic patterning by upregulating BMP signaling without affecting WNT signaling. Our study corroborates the function of RSPO2 as a BMP receptor antagonist and provides a proof-of-concept for pharmacologically uncoupling BMP antagonist from WNT agonist functions of RSPO2 using the inhibitor peptide RWd with enhanced target selectivity and limited side effects.

Keywords:  AML; BMP4 signaling; R-spondin2; TSP1; WNT signaling; Xenopus; cell differentiation; dendrimer; development; peptides

DOI:  https://doi.org/10.1016/j.jbc.2022.101586
Blood Adv. 2022 Jan 18. pii: bloodadvances.2021006325. [Epub ahead of print]

Patient-specific MDS-RS iPSCs define the mis-spliced transcript repertoire and chromatin landscape of SF3B1-mutant HSPCs.

Georgios Asimomitis, André G Deslauriers, Andriana G Kotini, Elsa Bernard, Davide Esposito, Malgorzata Olszewska, Nikolaos Spyrou, Juan Esteban Arango Ossa, Teresa Mortera-Blanco, Richard Patrick Koche, Yasuhito Nannya, Luca Malcovati, Seishi Ogawa, Mario Cazzola, Stuart A Aaronson, Eva Hellström-Lindberg, Elli Papaemmanuil, Eirini P Papapetrou.

SF3B1K700E is the most frequent mutation in myelodysplastic syndrome (MDS), but the mechanisms by which it drives MDS pathogenesis remain unclear. We derived a panel of 18 genetically matched SF3B1K700E and SF3B1WT induced pluripotent stem cell (iPSC) lines from patients with MDS with ring sideroblasts (MDS-RS) harboring isolated SF3B1K700E mutations and performed RNA- and ATAC- sequencing in purified CD34+/CD45+ hematopoietic stem/progenitor cells (HSPCs) derived from them. We developed a novel computational framework integrating splicing with transcript usage and gene expression analyses and derived a SF3B1K700E splicing signature consisting of 59 splicing events linked to 34 genes, which associates with the SF3B1 mutational status of primary MDS patient cells. The chromatin landscape of SF3B1K700E HSPCs showed increased priming towards the megakaryocyte- erythroid lineage. Transcription factor motifs enriched in chromatin regions more accessible in SF3B1K700E cells included, unexpectedly, motifs of the TEAD family. TEAD expression and transcriptional activity were upregulated in SF3B1-mutant iPSC-HSPCs, in support of a Hippo pathway-independent role of TEAD as a potential novel transcriptional regulator of SF3B1K700E cells. This study provides a comprehensive characterization of the transcriptional and chromatin landscape of SF3B1K700E HSPCs and nominates novel mis-spliced genes and transcriptional programs with putative roles in MDS-RS disease biology.

DOI: https://doi.org/10.1182/bloodadvances.2021006325
Blood Cancer J. 2022 Jan 17. 12(1): 7

European LeukemiaNet-defined primary refractory acute myeloid leukemia: the value of allogeneic hematopoietic stem cell transplant and overall response.

K H Begna, J Kittur, N Gangat, H Alkhateeb, M S Patnaik, A Al-Kali, M A Elliott, W J Hogan, M R Litzow, A Pardanani, C A Hanson, R P Ketterling, A Tefferi.

We sought to appraise the value of overall response and salvage chemotherapy, inclusive of allogeneic hematopoietic stem cell transplant (AHSCT), in primary refractory acute myeloid leukemia (prAML). For establishing consistency in clinical practice, the 2017 European LeukemiaNet (ELN) defines prAML as failure to attain CR after at least 2 courses of intensive induction chemotherapy. Among 60 consecutive patients (median age 63 years) correspondent with ELN-criteria for prAML, salvage was documented in 48 cases, 30/48 (63%) being administered intensive chemotherapy regimens and 2/48 consolidated with AHSCT as first line salvage. 13/48 (27%) attained response: CR, 7/13 (54%), CRi, 2/13 (15%), MLFS, 4/13 (31%). The CR/CRi rate was 9/48 (19%), with CR rate of 7/48 (15%). On univariate analysis, intermediate-risk karyotype was the only predictor of response (44% vs 17% in unfavorable karyotype; P = 0.04). Administration of any higher-dose (>1 g/m2) cytarabine intensive induction (P = 0.50), intensive salvage chemotherapy (P = 0.72), targeted salvage (FLT3 or IDH inhibitors) (P = 0.42), greater than 1 salvage regimen (P = 0.89), age < 60 years (P = 0.30), and de novo AML (P = 0.10) did not enhance response achievement, nor a survival advantage. AHSCT was performed in 12 patients with (n = 8) or without (n = 4) CR/CRi/MLFS. 1/2/5-year overall survival (OS) rates were 63%/38%/33% in patients who received AHSCT (n = 12) vs 27%/0%/0% in those who achieved CR/CRi/MLFS but were not transplanted (n = 5), vs 14%/0%/0% who were neither transplanted nor achieved CR/CRi/MLFS (n = 43; P < 0.001); the median OS was 18.6, 12.6 and 5.6 months, respectively. Although CR/CRi/MLFS bridged to AHSCT (n = 8), appeared to manifest a longer median OS (20 months), vs (13.4 months) for those with no response consolidated with AHSCT (n = 4), the difference was not significant P = 0.47. We conclude AHSCT as indispensable for securing long-term survival in prAML (p = 0.03 on multivariate analysis), irrespective of response achievement.

DOI: https://doi.org/10.1038/s41408-022-00606-8
Leukemia. 2022 Jan 20.

Outcomes based on treatment setting in refractory acute myeloid leukemia and other high-grade myeloid malignancies.

Noam E Kopmar, Megan Othus, Kelda M Gardner, Carole Shaw, Anna B Halpern, Bart L Scott, Paul C Hendrie, Roland B Walter, Pamela S Becker, Elihu H Estey, Mary-Elizabeth M Percival.

DOI: https://doi.org/10.1038/s41375-022-01509-0
Clin Adv Hematol Oncol. 2022 Jan;20(1): 37-46

Changing paradigms in the treatment of acute myeloid leukemia in older patients.

Alexandre Bazinet, Tapan M Kadia.

Standard therapy for acute myeloid leukemia (AML) has long consisted of intensive chemotherapy followed by allogeneic hematopoietic stem cell transplant. Older individuals (≥60 years), who constitute the majority of patients with AML, may not always benefit from such intensive approaches owing to increasing frailty, comorbidities, and a higher incidence of adverse-risk disease features. Recent years have seen major advances in the development of effective low-intensity therapies for AML. Low-intensity induction regimens based on hypomethylating agents, venetoclax, and nucleoside analogues are highly effective and safe. A greater emphasis is being placed on the importance of an accurate genetic classification of AML to identify patients who may benefit from novel targeted therapies, such as FLT3 and IDH inhibitors. Genomic classification also highlights a group of patients with high-risk disease (TP53-mutated), for whom improved treatments are urgently needed. Finally, given that relapse is the major cause of treatment failure in elderly patients with AML, innovative maintenance strategies incorporating targeted therapy are being investigated to delay or prevent relapse. In this article, we provide an updated review of the treatment of AML in older patients.
Expert Opin Investig Drugs. 2022 Jan 20.

Prospect of CAR T-cell therapy in acute myeloid leukemia.

Talha Badar, Alak Manna, Martha E Gadd, Mohamed A Kharfan-Dabaja, Hong Qin.

  INTRODUCTION: Long-term outcome of patients with acute myeloid leukemia (AML) remains dismal, especially for those with high-risk disease or who are refractory to conventional therapy. CAR T-cell therapy provides unique opportunity to improve outcome by specifically targeting leukemia cells through genetically engineered T-cells.AREAS COVERED: We summarize the progress of CAR T-cells therapy in AML. We examine its shortcomings in AML therapy and the strategies that are being implemented to improve its safety and effectiveness. PubMed Central, ClinicalTrials.gov and ASH annual meeting abstracts, were searched. Search terms used to identify clinical trials were "CAR T-cells in AML" OR CAR T-cells in leukemia". Relevant clinical trials and CAR T-cell research data was reviewed from June 2009 till July 2021.
EXPERT OPINION: CAR T-cell therapy has shown promise as a novel therapy, but there are number of barriers to overcome to achieve it full therapeutic potential in AML. Targeting leukemia specific antigen such as CLL1, to avoid myelotoxicity; incorporating checkpoint inhibitors to overcome leukemia induced immunosuppression and allogenic CAR T-cells to increases accessibility to patients with proliferative disease are among the strategies that are being explored to make CAR T-cell a successful immunotherapy for patient with AML.

Keywords:  CAR T-cells; CD123/CD33 CAR T-cells; CLL1 CAR T-cells; acute myeloid leukemia; allogeneic CAR; checkpoint inhibitors; gene editing; myelotoxicity secondary to AML CAR

DOI:  https://doi.org/10.1080/13543784.2022.2032642
Nature. 2022 Jan 20.

Life histories of myeloproliferative neoplasms inferred from phylogenies.

Nicholas Williams, Joe Lee, Emily Mitchell, Luiza Moore, E Joanna Baxter, James Hewinson, Kevin J Dawson, Andrew Menzies, Anna L Godfrey, Anthony R Green, Peter J Campbell, Jyoti Nangalia.

Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.

DOI: https://doi.org/10.1038/s41586-021-04312-6
iScience. 2022 Jan 21. 25(1): 103679

Recruitment of MLL1 complex is essential for SETBP1 to induce myeloid transformation.

Nhu Nguyen, Kristbjorn O Gudmundsson, Anthony R Soltis, Kevin Oakley, Kartik R Roy, Yufen Han, Carmelo Gurnari, Jaroslaw P Maciejewski, Gary Crouch, Patricia Ernst, Clifton L Dalgard, Yang Du.

  Abnormal activation of SETBP1 due to overexpression or missense mutations occurs frequently in various myeloid neoplasms and associates with poor prognosis. Direct activation of Hoxa9/Hoxa10/Myb transcription by SETBP1 and its missense mutants is essential for their transforming capability; however, the underlying epigenetic mechanisms remain elusive. We found that both SETBP1 and its missense mutant SETBP1(D/N) directly interact with histone methyltransferase MLL1. Using a combination of ChIP-seq and RNA-seq analysis in primary hematopoietic stem and progenitor cells, we uncovered extensive overlap in their genomic occupancy and their cooperation in activating many oncogenic transcription factor genes including Hoxa9/Hoxa10/Myb and a large group of ribosomal protein genes. Genetic ablation of Mll1 as well as treatment with an inhibitor of the MLL1 complex OICR-9429 abrogated Setbp1/Setbp1(D/N)-induced transcriptional activation and transformation. Thus, the MLL1 complex plays a critical role in Setbp1-induced transcriptional activation and transformation and represents a promising target for treating myeloid neoplasms with SETBP1 activation.

Keywords:  Biological sciences; Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2021.103679
Blood Adv. 2022 Jan 20. pii: bloodadvances.2021006827. [Epub ahead of print]

Reduced intensity hematopoietic stem cell transplantation for myelofibrosis in accelerated-phase.

Nico Gagelmann, Christine Wolschke, Rachel B Salit, Thomas Schroeder, Markus Ditschkowski, Victoria Panagiota, Bruno Cassinat, Felicitas Thol, Anita Badbaran, Marie Robin, Hans Christian Reinhardt, Francis Ayuk, Michael Heuser, Bart L Scott, Nicolaus Kröger.

Accelerated-phase (AP) myelofibrosis, currently defined by circulating blasts 10-19%, usually confers very high risk for progression and poor outcome. The outcome of hematopoietic stem cell transplantation for AP myelofibrosis has not been evaluated yet. We analyzed the outcome of 349 clinically and genetically annotated patients with primary or secondary myelofibrosis undergoing reduced intensity transplantation, of whom 35 had AP myelofibrosis. In comparison with chronic-phase (CP, <10% blasts), median leukocyte counts were higher, more patients had constitutional symptoms, and RAS mutations were detected more frequently in the AP group. After a median follow-up of 5.9 years, estimated 5-year overall survival was 65% (95% confidence interval, 49-81%) versus 64% (95% confidence interval, 59-69%) for the CP group (P=0.91), and median overall survival was not reached. In terms of relapse-free survival, estimated 5-year outcome for the AP group was 49% (95% confidence interval, 32-67%) versus 55% (95% confidence interval, 50-61%) for the CP group (P=0.65). Estimated 5-year non-relapse mortality was 20% (95% CI, 8-33%) for the AP group versus 30% (95% confidence interval, 24-35%; P=0.25) for the CP group. In terms of relapse, 5-year incidence was 30% (95% confidence interval, 14-46%) for the AP group versus 15% (95% confidence interval, 11-19%) for the CP group (P=0.02). Results were confirmed in multivariable analysis and propensity score matching. Increase in circulating blasts was associated with increased risk for relapse, showing strongest increase in risk for ≥10% blasts. In conclusion, reduced intensity transplantation showed excellent survival but higher relapse for AP myelofibrosis.

DOI: https://doi.org/10.1182/bloodadvances.2021006827
Leukemia. 2022 Jan 17.

Improved relative survival in older patients with acute myeloid leukemia over a 30-year period in the Netherlands: a long haul is needed to change nothing into something.

Z L Rana Kaplan, Nikki van Leeuwen, Eduardus F M Posthuma, Otto Visser, Gerwin Huls, Arjan A van de Loosdrecht, Avinash G Dinmohamed.

DOI: https://doi.org/10.1038/s41375-021-01503-y
Front Oncol. 2021 ;11 793274

The Elephant in The Room: AML Relapse Post Allogeneic Hematopoietic Cell Transplantation.

Iman Abou Dalle, Ali Atoui, Ali Bazarbachi.

  Relapsed acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (allo-HCT) is an unfavorable event associated with a poor prognosis, particularly for patients with early relapses. It usually arises from resistant leukemic blasts that escaped both preparative chemotherapy regimen and the graft-versus-leukemia (GVL) effect. Independent from the choice of salvage treatment, only minority of patients can achieve durable remissions. In recent years, better understanding of the disease relapse biology post allo-HCT allowed the application of newer strategies that could induce higher rates of remission, and potential longer survival. Those strategies aim at optimizing drugs that have a direct anti-leukemia activity by targeting different oncogenic mutations, metabolism pathways or surface antigens, and concurrently enhancing the immune microenvironment to promote GVL effect. This review discusses the current treatment landscape of AML relapse post allo-HCT.

Keywords:   immunotherapy; AML; Graft versus leukaemia (GVL); allotransplant; relapse

DOI:  https://doi.org/10.3389/fonc.2021.793274
Blood Adv. 2022 Jan 21. pii: bloodadvances.2021006076. [Epub ahead of print]

SFPQ-ABL1 and BCR-ABL1 utilize different signalling networks to drive B-cell acute lymphoblastic leukaemia.

Lauren M Brown, Soroor Hediyeh-Zadeh, Teresa Sadras, Hannah Huckstep, Jarrod J Sandow, Ray C Bartolo, Hansen J Kosasih, Nadia Davidson, Breon M Schmidt, Stefan Bjelosevic, Ricky W Johnstone, Andrew I Webb, Seong Lin Khaw, Alicia Oshlack, Melissa J Davis, Paul G Ekert.

Philadelphia-like (Ph-like) acute lymphoblastic leukaemia (ALL) is a high-risk subtype of B-cell ALL characterised by a gene expression profile resembling Philadelphia Chromosome positive ALL (Ph+ ALL) in the absence of BCR-ABL1. Tyrosine kinase activating fusions, some involving ABL1, are recurrent drivers of Ph-like ALL and are targetable with tyrosine kinase inhibitors (TKIs). We identified a rare instance of SFPQ-ABL1 in a child with Ph-like ALL. SFPQ-ABL1 expressed in cytokine-dependent cell lines was sufficient to transform cells which were sensitive to ABL1-targeting TKIs. In contrast to BCR-ABL1, SFPQ-ABL1 localised to the nuclear compartment and was a weaker driver of cellular proliferation. Phosphoproteomics analysis showed upregulation of cell cycle, DNA replication and spliceosome pathways, and downregulation of signal transduction pathways, including ErbB, NF-kappa B, VEGF, and MAPK signalling in SFPQ-ABL1-, compared to BCR-ABL1-expressing cells. SFPQ-ABL1 expression did not activate PI3K/AKT signalling and was associated with phosphorylation of G2/M cell cycle proteins. SFPQ-ABL1 was sensitive to navitoclax and S-63845 and promotes cell survival by maintaining expression of Mcl-1 and Bcl-xL. SFPQ-ABL1 has functionally distinct mechanisms by which it drives ALL, including subcellular localisation, proliferative capacity, and activation of cellular pathways, highlighting the role that fusion partners have in mediating the function of ABL1 fusions.

DOI: https://doi.org/10.1182/bloodadvances.2021006076
Blood. 2022 Jan 21. pii: blood.2021012830. [Epub ahead of print]

Structural Racism is a Mediator of Disparities in Acute Myeloid Leukemia Outcomes.

Ivy Elizabeth Abraham, Garth H Rauscher, Anand Ashwin Patel, William Pearse, Priya Rajakumar, Madelyn Burkart, Ahmed Aleem, Ami Dave, Sushma Bharadwaj, Koosha Paydary, Maria Acevedo-Mendez, Krishna Goparaju, Richard Gomez, Kylie Nei Carlson, Stephanie B Tsai, John G Quigley, John P Galvin, Maryam Zia, Melissa L Larson, Stephanie Berg, Wendy Stock, Jessica K Altman, Irum Khan.

Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic white (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult AML patients from six urban cancer centers and revealed inferior survival among NHB (HR=1.59, 95% CI: 1.15, 2.22) and Hispanic (HR=1.25, 95% CI: 0.88, 1.79) compared to NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across six composite variables: structural racism (census tract disadvantage, affluence and segregation), tumor biology (ELN risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization) and ICU admission during intensive chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, as well as treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.

DOI: https://doi.org/10.1182/blood.2021012830
Leukemia. 2022 Jan 17.

Inhibition of the deubiquitinating enzyme USP47 as a novel targeted therapy for hematologic malignancies expressing mutant EZH2.

Jing Yang, Ellen L Weisberg, Shuang Qi, Wei Ni, Husheng Mei, Zuowei Wang, Chengcheng Meng, Shengzhe Zhang, Mingqi Hou, Ziping Qi, Aoli Wang, Yunyun Jiang, Zongru Jiang, Tao Huang, Qingwang Liu, Robert S Magin, Laura Doherty, Wenchao Wang, Jing Liu, Sara J Buhrlage, Qingsong Liu, James D Griffin.

Activating mutations in EZH2, the catalytic component of PRC2, promote cell proliferation, tumorigenesis, and metastasis through enzymatic or non-enzymatic activity. The EZH2-Y641 gain-of-function mutation is one of the most significant in diffuse large B-cell lymphoma (DLBCL). Although EZH2 kinase inhibitors, such as EPZ-6438, provide clinical benefit, certain cancer cells are resistant to the enzymatic inhibition of EZH2 because of the inability to functionally target mutant EZH2, or because of cells' dependence on the non-histone methyltransferase activity of EZH2. Consequently, destroying mutant EZH2 protein may be more effective in targeting EZH2 mutant cancers that are dependent on the non-catalytic activity of EZH2. Here, using extensive selectivity profiling, combined with genetic and animal model studies, we identified USP47 as a novel regulator of mutant EZH2. Inhibition of USP47 would be anticipated to block the function of mutated EZH2 through induction of EZH2 degradation by promoting its ubiquitination. Moreover, targeting of USP47 leads to death of mutant EZH2-positive cells in vitro and in vivo. Taken together, we propose targeting USP47 with a small molecule inhibitor as a novel potential therapy for DLBCL and other hematologic malignancies characterized by mutant EZH2 expression.

DOI: https://doi.org/10.1038/s41375-021-01494-w
JCO Precis Oncol. 2020 Nov;4 639-646

Implications of Clonal Hematopoiesis for Precision Oncology.

Peter G Miller, David P Steensma.

Clonal hematopoiesis (CH) is common in middle-aged and elderly populations and confers a risk of hematological malignancy and also death due to cardiovascular disease. Prior therapy with cytotoxic chemotherapy or radiation increases the risk of CH, especially that associated with TP53 or PPM1D mutations. CH can complicate interpretation of cell-free or circulating tumor DNA assays, since most blood DNA is derived from hematopoietic cells. The specific determinants of clonal progression are unclear, but the gene carrying the mutation, size of the mutant clone, and presence of multiple mutations appear to increase risk of evolution to myeloid leukemia. While CH is not yet modifiable, specific mutations such as TET2 or IDH1/IDH2 confer vulnerabilities to established drugs or developmental compounds, and investigators are developing clinical trials to try to exploit these vulnerabilities.

DOI: https://doi.org/10.1200/PO.20.00144
Cancer Discov. 2022 Jan 19.

Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants.

Marco H Hofmann, Daniel Gerlach, Sandra Misale, Mark Petronczki, Norbert Kraut.

KRAS is the most frequently mutated oncogene, harboring mutations in approximately one in seven cancers. Allele-specific KRASG12C inhibitors are currently changing the treatment paradigm for patients with KRAS G12C-mutated non-small cell lung cancer and colorectal cancer. The success of addressing a previously elusive KRAS allele has fueled drug discovery efforts for all KRAS mutants. Pan-KRAS drugs have the potential to address broad patient populations, including KRAS G12D-, KRAS G12V-, KRAS G13D-, KRAS G12R-, and KRAS G12A-mutant or KRAS wild-type-amplified cancers, as well as cancers with acquired resistance to KRASG12C inhibitors. Here, we review actively pursued allele-specific and pan-KRAS inhibition strategies and their potential utility. SIGNIFICANCE: Mutant-selective KRASG12C inhibitors target a fraction (approximately 13.6%) of all KRAS-driven cancers. A broad arsenal of KRAS drugs is needed to comprehensively conquer KRAS-driven cancers. Conceptually, we foresee two future classes of KRAS medicines: mutant-selective KRAS drugs targeting individual variant alleles and pan-KRAS therapeutics targeting a broad range of KRAS alterations.

DOI: https://doi.org/10.1158/2159-8290.CD-21-1331