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Leukemias driven by chromosomal translocation of the mixed-lineage leukemia gene ( or ) are highly prevalent in pediatric oncology. The poor survival rate and lack of an effective targeted therapy for patients with -rearranged ( -r) leukemias emphasize an urgent need for improved knowledge and novel therapeutic approaches for these malignancies. The resulting chimeric products of gene rearrangements, i.e., MLL-fusion proteins (MLL-FPs), are capable of transforming hematopoietic stem/progenitor cells (HSPCs) into leukemic blasts. The ability of MLL-FPs to reprogram HSPCs toward leukemia requires the involvement of multiple chromatin effectors, including the histone 3 lysine 79 methyltransferase DOT1L, the chromatin epigenetic reader BRD4, and the super elongation complex. These epigenetic regulators constitute a complicated network that dictates maintenance of the leukemia program, and therefore represent an important cluster of therapeutic opportunities. In this review, we will discuss the role of MLL and its fusion partners in normal HSPCs and hematopoiesis, including the links between chromatin effectors, epigenetic landscapes, and leukemia development, and summarize current approaches to therapeutic targeting of -r leukemias.

Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5’-KMT2A, two patients had a 5’-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.

Inosine monophosphate dehydrogenase (IMPDH) is a rate‐limiting enzyme in de novo guanine nucleotide synthesis pathway. Although IMPDH inhibitors are widely used as effective immunosuppressants, their antitumor effects have not been proven in the clinical setting. Here, we found that acute myeloid leukemias (AMLs) with MLL‐fusions are susceptible to IMPDH inhibitors in vitro . We also showed that alternate‐day administration of IMPDH inhibitors suppressed the development of MLL‐AF9‐driven AML in vivo without having a devastating effect on immune function. Mechanistically, IMPDH inhibition induced overactivation of Toll‐like receptor (TLR)‐TRAF6‐NF‐κB signaling and upregulation of an adhesion molecule VCAM1, which contribute to the antileukemia effect of IMPDH inhibitors. Consequently, combined treatment with IMPDH inhibitors and the TLR1/2 agonist effectively inhibited the development of MLL‐fusion AML. These findings provide a rational basis for clinical testing of IMPDH inhibitors against MLL‐fusion AMLs and potentially other aggressive tumors with active TLR signaling. Synopsis This study describes the potent antileukemia effect of IMPDH inhibitors on MLL‐fusion leukemias, which is partly mediated by the overactivation of TLR‐NF‐kB‐Vcam1 pathway. MLL‐fusion leukemias are particularly susceptible to IMPDH inhibition. An alternate‐day administration of IMPDH inhibitors effectively suppresses MLL‐AF9‐driven leukemogenesis in vivo through myeloid differentiation without any devastating effect on immune function. IMPDH inhibition results in activation of TLR pathway and Vcam1 upregulation in MLL‐fusion leukemia cells. Combined treatment with IMPDH inhibitors and the TLR1/2 agonist shows potent antileukemia effects in vivo . Graphical Abstract This study describes the potent antileukemia effect of IMPDH inhibitors on MLL‐fusion leukemias, which is partly mediated by the overactivation of TLR‐NF‐kB‐Vcam1 pathway.

Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. In cord blood-derived CD34+ cells, enforced expression of ZNF521 provides a significant proliferative advantage and enhances MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34+ cultures displayed subsets of genes up-regulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, at either the early or late time points of an in vitro leukemogenesis model. The silencing of ZNF521 in the MLL-AF9 + THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating the effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining the self-renewal of the immature AML compartment, most likely through the perturbation of the gene expression landscape, which ultimately favors the expansion of MLL-AF9-transformed leukemic clones.

5-Lipoxygenase (5-LO), encoded by the gene ALOX5 , is implicated in several pathologies. As key enzyme in leukotriene biosynthesis, 5-LO plays a central role in inflammatory diseases, but the 5-LO pathway has also been linked to development of certain hematological and solid tumor malignancies. Of note, previous studies have shown that the leukemogenic fusion protein MLL-AF4 strongly increases ALOX5 gene promoter activity. Here, we investigate the upregulation of ALOX5 gene expression by MLL-AF4. Using reporter assays, we first identified the tandem GC box within the ALOX5 promotor sequence as the main target of MLL-AF4. Subsequently, we narrowed down the domains within the MLL-AF4 protein responsible for ALOX5 promoter activation. Our findings indicate that MLL-AF4 binds to the ALOX5 promoter via its CXXC domain and that the AF9ID, pSER and CHD domains redundantly activate transcriptional elongation. Knockdown of the MLL-AF4 gene in the human B cell line SEM revealed that MLL-AF4 is an inducer of ALOX5 gene expression in leukemic cells with lymphoid properties. Finally, we found that the MLL-AF4-related protein MLL-AF9, a driver of acute myeloid leukemia, similarly acts on the ALOX5 promoter. Taken together, we show that two prominent MLL fusion proteins are ALOX5 gene inducers in cells with lymphoid features.

The t(10;11)(p12;q23) translocation and the t(10;11)(p12;q14) translocation, which encode the MLL (mixed lineage leukemia)–AF10 and CALM (clathrin assembly lymphoid myeloid leukemia)–AF10 fusion oncoproteins, respectively, are two recurrent chromosomal rearrangements observed in patients with acute myeloid leukemia and acute lymphoblastic leukemia. Here, we demonstrate that MLL–AF10 and CALM–AF10-mediated transformation is dependent on the H3K79 methyltransferase Dot1l using genetic and pharmacological approaches in mouse models. Targeted disruption of Dot1l using a conditional knockout mouse model abolished in vitro transformation of murine bone marrow cells and in vivo initiation and maintenance of MLL–AF10 or CALM–AF10 leukemia. The treatment of MLL–AF10 and CALM–AF10 transformed cells with EPZ004777, a specific small-molecule inhibitor of Dot1l, suppressed expression of leukemogenic genes such as Hoxa cluster genes and Meis1 , and selectively impaired proliferation of MLL–AF10 and CALM–AF10 transformed cells. Pretreatment with EPZ004777 profoundly decreased the in vivo spleen-colony-forming ability of MLL–AF10 or CALM–AF10 transformed bone marrow cells. These results show that patients with leukemia-bearing chromosomal translocations that involve the AF10 gene may benefit from small-molecule therapeutics that inhibit H3K79 methylation.

Balanced rearrangements involving the KMT2A gene, located at 11q23, are among the most frequent chromosome aberrations in acute myeloid leukemia (AML). Because of numerous fusion partners, the mutational landscape and prognostic impact of specific 11q23/KMT2A rearrangements are not fully understood. We analyzed clinical features of 172 adults with AML and recurrent 11q23/KMT2A rearrangements, 141 of whom had outcome data available. We compared outcomes of these patients with outcomes of 1,097 patients without an 11q23/KMT2A rearrangement categorized according to the 2017 European LeukemiaNet (ELN) classification. Using targeted next-generation sequencing, we investigated the mutational status of 81 leukemia/cancer-associated genes in 96 patients with 11q23/KMT2A rearrangements with material for molecular studies available. Patients with 11q23/KMT2A rearrangements had a low number of additional gene mutations (median, 1; range 0 to 6), which involved the RAS pathway (KRAS, NRAS, and PTPN11) in 32% of patients. KRAS mutations occurred more often in patients with t(6;11)(q27;q23)/KMT2A-AFDN compared with patients with the other 11q23/KMT2A subsets. Specific gene mutations were too infrequent in patients with specific 11q23/KMT2A rearrangements to assess their associations with outcomes. We demonstrate that younger (age 60 y) patients with t(9;11)(p22;q23)/KMT2A-MLLT3 had better outcomes than patients with other 11q23/KMT2A rearrangements and those without 11q23/KMT2A rearrangements classified in the 2017 ELN intermediate-risk group. Conversely, outcomes of older patients (age ≥60 y) with t(9;11)(p22;q23) were poor and comparable to those of the ELN adverse-risk group patients. Our study shows that patients with an 11q23/KMT2A rearrangement have distinct mutational patterns and outcomes depending on the fusion partner.

Abstract Introduction/Objective Presence of distinct MLL rearrangements is an independent dismal prognostic factor. Rearrangements of the histone lysine [K]- MethylTransferase 2A gene (KMT2A) on chromosome 11q23, formerly known as the mixed-lineage leukemia (MLL) gene, are found in 10% and 5% of adult and children with acute leukemia respectively. Chromosome 11 breakpoints are typically localized to band 11q23.3, frequently altering the proto- oncogene KMT2A/MLL whereas partner chromosomes involved in translocation may vary. More than 80 different gene partners involved in this fusion have been described, although the majority of leukemias results from 6 common partner genes. KMT2A gene rearrangement are associated with poor prognosis in both Lymphoid and Myeloid leukemia. Methods/Case Report A retrospective study conducted in Cytogenetic laboratory of The Indus hospital, Karachi. All karyotype cases (age 1-60 year) with chromosome 11 aberrations were included from October 2020 to December 2022. Karyotype and FISH performed using G-banding and break a part probe for MLL respectively. Results (if a Case Study enter NA) Total of 923 cases received for karyotyping out of which 32(3.4%) cases were reported for 11q23 abnormalities. The median age was 5 (1.25-12.5) years, majority 15 (47%) were 1-10 years, 9(28%) were >10 years and 7(22%) were <1 years. M:F ratio was 1.9:1. B-ALL were 19(59.4%), AML 8(25%), and 5 (15.6%) were others. FISH performed in 23(72%) cases, 21 (91%) showed concordance with karyotype. The t(9;11) was the commonest 7(22%), followed by t(4;11) and (1;11). Chromosome 9 was the most common partner identified in B-ALL. Loss of 11q23 observed in 3 (13%) cases. Conclusion The findings underscore the heterogeneity of partner chromosomes involved in KMT2A gene rearrangements and emphasize the importance of employing both FISH and karyotyping for comprehensive detection. The high concordance rate between the two methods supports their complementary roles in clinical diagnostics. Understanding the specific translocations and partner chromosomes associated with MLL gene rearrangements contributes valuable insights for prognostication and targeted therapeutic strategies in acute leukemia. FISH and karyotype showed 91% concordance to detect this aberration.