Elsevier

Blood Reviews

Volume 34, March 2019, Pages 26-33
Blood Reviews

Review
Prognostic and therapeutic role of CLEC12A in acute myeloid leukemia

https://doi.org/10.1016/j.blre.2018.10.003Get rights and content

Abstract

CLEC12A has recently been identified as an antigen, expressed on leukemic stem cells and leukemic blasts. Given the fact that this expression profile seems stable throughout diagnosis, treatment and relapse on leukemic blasts and leukemic stem cells, CLEC12A can be considered a highly potent and reliable marker for the detection of measurable residual disease and therefore applicable for risk stratification and prognostication in AML. Low CLEC12A expression on leukemic blasts seems to be independently associated with lower likelihood of achieving complete remission after 1 cycle of induction chemotherapy, shorter event free survival, as well as overall survival, indicating potential prognostic properties of CLEC12A expression itself.

Lack of expression on the normal hematopoietic stem and progenitor cells, in contrast to CD123 and CD33, might result in less toxicity regarding cytopenias, making CLEC12A an interesting target for innovating immunotherapies, including monoclonal and bispecific antibodies, antibody-drug conjugates and CAR-T cells therapy.

Introduction

Primarily due to advances in supportive care and broader access to allogeneic hematopoietic cell transplantation (HCT), outcomes in children, adolescents and younger adults with acute myeloid leukemia (AML) have gradually improved over the last 40 years [[1], [2], [3]]. For older adults, progress has been much more limited. Overall, AML in adults remains difficult to treat and even with recent approval of several new drugs (midostaurin, gemtuzumab ozogamicin, CPX-351, enasidenib and ivosidenib) [4,5], a minority of patients are expected to be alive 2–5 years after diagnosis. Since most patients ultimately die from their disease or consequences of treatment toxicities, the need for effective, relatively well-tolerated drugs that augment or replace current therapies is unquestioned.

Antibody-based therapies have long been pursued for the treatment of AML [6,7]. Several randomized studies have demonstrated improved survival for subsets of people with AML with the CD33 antibody-drug conjugate, gemtuzumab ozogamicin [8], validating the concept of antigen-directed therapy for this malignancy. With increasing understanding of the role of leukemic stem cells (LSCs) for disease persistence/recurrence and steady refinements in our knowledge on their phenotypic characteristics, there is growing interest in using antibodies to identify and eradicate such cells [[9], [10], [11], [12], [13], [14]]. Ideally, for diagnostic, prognostic and therapeutic purposes, target antigens/epitopes should be specific for LSCs and malignant progeny, with little to no expression on normal cells. Quite a number of LSC-associated antigens have been described, including CD25, CD32, CD96 and CD123 [[9], [10], [11], [12], [13], [14]]. Emerging data indicate CLEC12A (C-type lectin domain family 12, member A; also known as C-type lectin-like molecule-1 [CLL-1], CD371, dendritic cell-associated lectin 2 [DCAL2], myeloid inhibitory C-type lectin-like receptor [MICL] and killer cell lectin like receptor-1 [KLRL1]) may be of particular interest for both risk prognostication as well as a therapeutic target because of its expression on LSCs. Here, we will review the expression profile of CLEC12A and appraise its potential as a prognostic marker, including a possible role for monitoring of measurable (‘minimal’) residual disease (MRD). We will also summarize current efforts in targeting CLEC12A with a variety of therapeutics such as unconjugated monospecific antibodies, antibody-drug conjugate, bispecific antibodies and chimeric antigen receptor (CAR)-modified T-cells.

Section snippets

Structure and function of CLEC12A

CLEC12A is a type II transmembrane glycoprotein and member of the C-type lectin superfamily, which, based on phylogeny and domain organization, is divided into 17 subgroups [15,16]. This superfamily has been implicated in a wide variety of cellular functions related to phagocytosis, pathogen recognition, complement activation and cell adhesion [17,18]. The CLEC12A gene is located on chromosome 12p13 in a region near a cluster of C-type lectins/NK gene complex [19,20] and encodes 6 exons [21,22

CLEC12A as a predictive marker for survival

As discussed above, CLEC12A expression may be associated with cytogenetic and molecular abnormalities in AML [36]. Using a cut off expression level of 42,5%, 123 bone marrow samples of CD34+ AML patients were divided into CLEC12A low and high expression. The low expression group seemed to be significantly correlated to a poor karyotype (low: 19 of 46 cases, 41.30% versus high: 16 of 73 cases, 21.91%) (P < .05). In molecular profiling (FLT3-ITD, CEBPA, c-KIT, NPM-1 being reported) only biallelic

CLEC12A as a marker for MRD monitoring

Primarily due to advances in supportive care and broader access to allogeneic HCT, outcomes in patients with AML have gradually improved over the last 40 years [[1], [2], [3]]. Unfortunately, a large proportion of patients relapse, due to persistent chemo resistant malignant cells [37,42], undetectable by morphology, now referred to as measurable residual disease (MRD). There are multiple reasons to apply MRD detection in AML: 1) to provide an objective methodology to establish a deeper

Therapeutic properties of CLEC12A

Demonstrated expression of CLEC12A on AML blasts and, in particular, immature AML cells, but not within the normal stem/progenitor cell compartment, has raised interest in developing CLEC12A-directed immunotherapies. Multiple strategies have been undertaken so far that are based on unconjugated monospecific antibodies, antibody-drug conjugates, bispecific antibodies and CAR-modified T-cells.

Limitations and toxicities

Given the display of CLEC12A on normal immature and mature myeloid cells, it is very likely that highly-potent CLEC12A-directed therapeutics such as bispecific antibodies or CAR T-cells will eliminate cells such as CMPs, granulocytes, macrophages and monocytes and thereby increase the risk of infectious complications, posing a challenge for the safe use of such agents in clinical practice. Additionally, CLEC12A directed CAR-T cells may cause long lasting cytopenias, due to their desired ongoing

Conclusion and future challenges

Since the discovery of CLEC12A as an expression marker on the surface of multiple myeloid hematopoietic cells, its potential in diagnosis, follow up, risk stratification and treatment modalities in acute myeloid leukemia, has been explored. Selective expression on leukemic blasts and leukemic stem cells in AML patients, in contrast to the lack of expression on the stem cell compartment of healthy persons, makes it an attractive diagnostic marker for detection of MRD.

In this modality, CLEC12A

Practice points

  • CLEC12A is being expressed on leukemic blasts in a large proportion of AML patients and can, in a lesser extent, also be determined on leukemic stem cells

  • In normal hematopoiesis, CLEC12A expression emerges at the level of the common myeloid progenitor, extending towards the mature myeloid lineage

  • Low CLEC12A expression on leukemic blasts seems to be related to poor outcome in AML

  • CLEC12A is a stable marker for detection of measurable residual disease in AML

  • CLEC12A seems to be a suitable target

Research agenda

  • What is the physiological ligand of CLEC12A in humans?

  • What is the physiological function of CLEC12A in humans?

  • Is low CLEC12A expression related to poor chemo sensitivity and what are the underlying mechanisms?

  • What is the underlying mechanism of the association between the level of CLEC12A expression and certain genetic and chromosomal abnormalities?

  • For which disease stage should CLEC12A-targeted therapies be used?

  • Is CLEC12A-directed therapy effectively eliminating AML stem cells?

  • Which subset of

Disclosures/conflicts of interest

L.M.M.: no disclosures.

R.B.W.: received laboratory research grants and/or clinical trial support from Actinium Pharmaceuticals, Inc., Amgen Inc., Amphivena Therapeutics, Inc., Aptevo Therapeutics, Inc., Covagen AG, and Seattle Genetics, Inc.; has ownership interests with Amphivena Therapeutics, Inc.; and is (or has been) a consultant to Amphivena Therapeutics, Inc., Boehringer Ingelheim Pharma GmbH & Co. KG, Covagen AG, Emergent Biosolutions, Inc. (now Aptevo Therapeutics, Inc.), Pfizer, Inc.,

Acknowledgments

R.B.W. is a Leukemia & Lymphoma Society Scholar in Clinical Research. T.M. Westers and A. van Rhenen analyzed and provided the unpublished data concerning CLEC12A expression in MDS.

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